Generated by All in One SEO v5.0.0.1, this is an llms.txt file, used by LLMs to index the site. # Kids First Working together to put Kids First ## Sitemaps - [XML Sitemap](https://kidsfirstdrc.org/sitemap.xml): Contains all public & indexable URLs for this website. ## Posts - [News](https://kidsfirstdrc.org/news/) - Stay up to date with the latest information on data releases, studies and publications from the Kids First Data Resource Center - [From Questions to Action: A Parent’s Journey with Kids First Data](https://kidsfirstdrc.org/from-questions-to-action-a-parents-journey-with-kids-first-data/) - Dana Maier’s search for answers began before her son was even born. During pregnancy, an abnormal finding on an ultrasound led to more scans, specialist visits, and questions about her baby’s kidneys and heart. Despite extensive testing, the full picture remained unclear until doctors confirmed that her son had situs inversus, a rare condition in An abnormal ultrasound raised questions about her baby’s kidneys and heart. A researcher introduced her to the Kids First DRC portal. - [Turner Lab Tools on CAVATICA Show What’s Possible with Kids First Data](https://kidsfirstdrc.org/turner-lab-tools-on-cavatica-show-whats-possible-with-kids-first-data/) - Access to data alone does not drive discovery. Several research platforms now make large datasets available, but the work of turning that data into meaningful insight can still be slow. Researchers often need to build or assemble their own analysis tools before they can begin answering scientific questions. The Gabriella Miller Kids First Data Resource - [Kids First Data Instrumental in New Understanding of Childhood Brain Tumors](https://kidsfirstdrc.org/kids-first-data-instrumental-in-new-understanding-of-childhood-brain-tumors/) - Articles - August 11, 2025 - The seemingly insurmountable challenge presented by childhood brain tumors, particularly high-grade gliomas (HGG), has long presented a formidable challenge. However, leading-edge research from scientists at the Children's Brain Tumor Network (CBTN) is introducing new hope by revolutionizing our understanding of these diseases. This hope is built upon the robust data available only through the Gabriella - [NCI Pre-Application Webinar for RFA-CA-19-033: Improving Outcomes for Pediatric, Adolescent and Young Adult Cancer Survivors](https://kidsfirstdrc.org/nci-pre-application-webinar-for-rfa-ca-19-033-improving-outcomes-for-pediatric-adolescent-and-young-adult-cancer-survivors/) - On January 31, 2019 from 1:00 to 2:00 p.m. EST, the National Cancer Institute’s (NCI) Division of Cancer Control and Population Sciences (DCCPS) will host a webinar to discuss the Funding Opportunity Announcement (FOA) RFA-CA-19-033, Improving Outcomes for Pediatric, Adolescent and Young Adult Cancer Survivors (U01 Clinical Trial Required). This webinar will explain the goals and objectives - [Revolutionizing Pediatric Research: Unveiling the Enhanced Beta Portal](https://kidsfirstdrc.org/revolutionizing-pediatric-research-unveiling-the-enhanced-beta-portal/) - A New Chapter in Pediatric Research In a landmark move poised to transform research for rare congenital disorders and childhood cancers, the Gabriella Miller Kids First Pediatric Research Program Data Resource Center (Kids First DRC, or Kids First Data Resource Center) has unveiled the upgraded Kids First Data Resource Portal (Kids First Portal), bringing with - [NIH Kids First Program announces the release of three new pediatric research datasets exploring childhood rare disease](https://kidsfirstdrc.org/nih-kids-first-program-announces-the-release-of-three-new-pediatric-research-datasets-exploring-childhood-rare-disease/) - These new datasets further support the effort to understand the genetic causes and links between childhood cancers and congenital disorders. WHO: The Gabriella Miller Kids First Pediatric Research Program (Kids First), an initiative of the National Institutes of Health (NIH) WHAT: Kids First announces the release of three comprehensive new pediatric research datasets exploring childhood - [Children’s Brain Tumor Network Dataset Now Accessible on Kids First Data Resource Center Portal](https://kidsfirstdrc.org/cbtndataset/) - View this press release on PR Newswire The Gabriella Miller Kids First Data Resource Center (Kids First DRC) announces the addition of the full Children’s Brain Tumor Network (CBTN) dataset to the Kids First DRC portal. This significant milestone provides researchers worldwide with unprecedented access to a vast repository of pediatric brain tumor data, paving - [New Data Sets from NIH Kids First Program Accelerate Rare Childhood Disease Research](https://kidsfirstdrc.org/q1fy25-datasets/) - This article was published as a news release on EurekAlert, shared on Feb 5, 2025. The new Kids First datasets advance our understanding of how genetics contribute to childhood cancers and congenital disorders, opening new doors for prevention and treatment. WHO: The Gabriella Miller Kids First Pediatric Research Program (Kids First), an initiative of the - [Cross-Institution Database Drives New Pediatric Research Opportunity](https://kidsfirstdrc.org/ccdi/) - Childhood cancer research has taken a monumental step forward with the launch of the Childhood Cancer Data Initiative (CCDI), a groundbreaking effort spearheaded by the National Cancer Institute (NCI). Childhood Cancer Data Initiative (CCDI) is a collaborative community endeavor supported by a 10-year, $500-million federal investment. It aims to learn from every patient diagnosed with Cross-Institution Database Drives New Pediatric Research Opportunity - [First-Ever Long Read Datasets Added to Two Kids First Studies](https://kidsfirstdrc.org/first-ever-long-read-datasets-added-to-two-kids-first-studies/) - This article was originally published as a news release via EurekAlert This new Kids First data creates a fuller understanding of how genetics contributes to childhood cancers and congenital disorders, opening additional doors for prevention and treatment. WHO: The Gabriella Miller Kids First Pediatric Research Program (Kids First), an initiative of the National Institutes of - [Kids First: A New Vision for Pediatric Research](https://kidsfirstdrc.org/kids-first-a-new-vision-for-pediatric-research/) - In the world of childhood cancer and congenital disorder research, ten years is more than a milestone—it’s a movement. Each year in the United States, nearly 16,000 children are diagnosed with cancer before their 20th birthday. Three percent of all children are born with congenital disorders like orofacial clefts or heart defects. Each one of - [New Study and Major Data Updates Expand the Kids First Data Ecosystem](https://kidsfirstdrc.org/new-study-and-major-data-updates-expand-the-kids-first-data-ecosystem/) - Originally released on Eurekalert on September 8, 2025 The Gabriella Miller Kids First Pediatric Research Program (Kids First) has released its 36th study and introduced significant new data updates to two existing studies, further advancing efforts to uncover the genetic foundations of childhood cancers and congenital conditions. This brings the total data files available at - [The Gabriella Miller Kids First Data Resource Center has launched the Variant Workbench](https://kidsfirstdrc.org/the-gabriella-miller-kids-first-data-resource-center-has-launched-the-variant-workbench/) - This press release was distributed on October 14, 2025, via EurekAlert. The Gabriella Miller Kids First Data Resource Center (Kids First DRC) has launched the Variant Workbench, an innovative tool designed to dramatically accelerate research into childhood diseases. For researchers studying genetic diseases, this new resource shifts the focus from the complex, time-consuming task of managing - [What If Data Could Save a Life?](https://kidsfirstdrc.org/what-if-data-could-save-a-life/) - What if data could save a life? Discover how Kids First is transforming pediatric data sharing through AI, collaboration, and compassion. - [Kids First Releases Landmark Dataset on Rare Childhood Germ Cell Tumors](https://kidsfirstdrc.org/kids-first-releases-landmark-dataset-on-rare-childhood-germ-cell-tumors/) - The Gabriella Miller Kids First Data Resource Center adds vital genomic data on rare childhood germ cell tumors in its newly released 37th study. - [Uniting Genomics for Kids at ASHG 2025](https://kidsfirstdrc.org/uniting-genomics-for-kids-at-ashg-2025/) - Kids First experienced an incredible week at the American Society of Human Genetics 2025 Annual Meeting - [The Rare We Share](https://kidsfirstdrc.org/the-rare-we-share/) - Learn more and see what connects us all through the rare we share. - [A Decade of Kids First](https://kidsfirstdrc.org/a-decade-of-kids-first/) - What It Took to Change How Pediatric Science Gets Done When the Gabriella Miller Kids First Pediatric Research Program (Kids First) launched, the premise was ambitious. If we could bring together deeply annotated pediatric data across cancer and congenital disorders, make it open and usable, and pair it with the right technology and community, - [NIH Kids First program releases nine new data sets for childhood cancer and congenital disorder research](https://kidsfirstdrc.org/nih-kids-first-program-releases-nine-new-data-sets-for-childhood-cancer-and-congenital-disorder-research/) - Philadelphia, PA., October 24, 2023 WHO: The Gabriella Miller Kids First Pediatric Research Program (Kids First), an initiative of the National Institutes of Health (NIH) WHAT: Kids First announces the release of nine robust new pediatric research datasets spanning childhood cancers, congenital disorders, and cross-condition data. New publicly available datasets include: PEDIATRIC CROSS-CONDITION Kids First and INCLUDE: - [American Cleft Palate-Craniofacial Association](https://kidsfirstdrc.org/479-2/) - "The American Cleft Palate-Craniofacial Association (ACPA) has advocated for a team care approach for oral cleft and craniofacial patients for 76 years. We support the Kids First Data Resource Center because like ACPA, Kids First understands that collaboration results in better outcomes. We strongly support Kids First's work to gather medical research and bridge the - [Fostering Synergy: Highlights from the Kids First/INCLUDE Ancillary Session at ASHG 2023](https://kidsfirstdrc.org/fostering-synergy-highlights-from-the-kids-first-include-ancillary-sessionat-ashg-2023/) - In the dynamic ambiance of ASHG 2023 in Washington, DC, the collaborative poster session, led by the NIH Common Fund’s Gabriella Miller Kids First Pediatric Research Program (Kids First) and the NIH Investigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE), united researchers and stakeholders. The primary objective? Showcasing cutting-edge research emerging - [VALUABLE NEW DATASET GIVES INSIGHT INTO LINKS AMONG PEDIATRIC CONDITIONS](https://kidsfirstdrc.org/valuable-new-dataset-gives-insight-into-links-among-pediatric-conditions/) - The NIH Common Fund's Gabriella Miller Kids First Pediatric Research Program (Kids First) and the INCLUDE Project (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE), announce the release of a robust, new cross-condition research dataset spanning Down syndrome (DS), leukemia, and heart defects. Kids First and INCLUDE are working to help researchers uncover new insights into - [INVESTIGATOR SPOTLIGHT: Nara Sobreira, MD, PhD](https://kidsfirstdrc.org/investigator-spotlight-nara-sobreira-md-phd/) - Dr. Sobreira is an Assistant Professor at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins School of Medicine with primary interest in rare Mendelian phenotypes and analysis of next-generation sequencing. Her main clinical and research focus is on identifying the molecular basis of phenotypes associated with cartilage tumors and vascular anomalies (mainly Ollier disease - [The Gabriella Miller Kids First Pediatric Research Program’s Childhood Cancer and Structural Birth Defect Cohort Sequencing Opportunity](https://kidsfirstdrc.org/the-gabriella-miller-kids-first-pediatric-research-programs-childhood-cancer-and-structural-birth-defect-cohort-sequencing-opportunity/) - The Gabriella Miller Kids First Pediatric Research Program Announce An Opportunity to Sequence Childhood Cancer and Structural Birth Defect Cohorts The NIH Common Fund’s Gabriella Miller Kids First Pediatric Research Program (Kids First) recently announced a new opportunity for researchers working with childhood cancer or structural birth defect cohorts. Kids First is now soliciting applications - [FOUNDATION SPOTLIGHT: The Dragon Master Foundation](https://kidsfirstdrc.org/foundation-spotlight-the-dragon-master-foundation/) - The Dragon Master Foundation’s mission is to find and accelerate cures for cancers and other diseases by finding and rewarding a community of collaboration and innovation. They seek to spread awareness, expedite research and kinder treatments, and improve the quality of life for patients and their families. To learn more about The Dragon Master Foundation, visit - [Kids First DRC Attending 2019 AACR Annual Meeting](https://kidsfirstdrc.org/kids-first-drc-attending-2019-aacr-annual-meeting/) - The Annual Meeting of the American Association for Cancer Research (AACR) covers the latest discoveries across the spectrum of cancer research—from population science and prevention; to cancer biology, translational, and clinical studies; to survivorship and advocacy—and highlights the work of the best minds in cancer research and medicine from institutions all over the world. AACR - [INVESTIGATOR SPOTLIGHT: Dawn Siegel, MD](https://kidsfirstdrc.org/investigator-spotlight-dawn-siegel-md/) - Dr. Siegel has a particular interest in general pediatric dermatology and skin health in infants, children, and adolescents. Dr. Siegel focuses on improving the quality of life of children and their families by treating skin conditions such as acne, eczema, and psoriasis. She also has an expertise in genetic skin syndromes. She has spent the - [Rare Disease Day at NIH](https://kidsfirstdrc.org/rare-disease-day-at-nih/) - Kids First DRC Poster at the NIH and NCATS Rare Disease Day Rare Disease Day takes place on the last day of February each year. The main objective of Rare Disease Day is to raise awareness amongst the general public and decision-makers about rare diseases and their impact on patients' lives. Since Rare Disease Day - [FOUNDATION SPOTLIGHT: PHACE Syndrome Community](https://kidsfirstdrc.org/foundation-spotlight-phace-syndrome-community/) - The mission of PHACE Syndrome Community is to support research and advocacy around the cause and treatment of PHACE, to create and support the community of affected families, to sponsor conventions, meetings, and gatherings for the community and the doctors supporting the community, and to perform fundraising to support the mission. To learn more, visit - [Gabriella Miller Kids First Data Resource Center at the 2019 AACR Annual Meeting](https://kidsfirstdrc.org/gabriella-miller-kids-first-data-resource-center-at-the-2019-aacr-annual-meeting/) - Gabriella Miller Kids First Data Resource Center at the 2019 Annual Meeting of the American Association for Cancer Research The Annual Meeting of the American Association for Cancer Research (AACR) covers the latest discoveries across the spectrum of cancer research—from population science and prevention; to cancer biology, translational, and clinical studies; to survivorship and advocacy—and highlights the - [INVESTIGATOR SPOTLIGHT: Adam Resnick, PhD](https://kidsfirstdrc.org/investigator-spotlight-adam-resnick-phd/) - Dr. Resnick is the Principal Investigator of the Kids First Data Resource Center and Director of the Center for Data Driven Discovery in Biomedicine at Children’s Hospital of Philadelphia. He also serves as Scientific Co-chair for the Children’s Brain Tumor Tissue Consortium and the Pacific Pediatric Neurologist-Oncology Consortium. His research is focused on defining the - [Kids First DRC at PedSNO 2019](https://kidsfirstdrc.org/kids-first-drc-at-pedsno-2019/) - Since 2011, the Society for Neuro-Oncology has hosted a biennial conference for pediatric basic and translational neuro-oncology (PedSNO). The conference encourages the sharing of ideas, results, and new collaborations, and offers attendees a state-of-the-art update in the field of pediatric brain tumor research. The 5th PedSNO Conference was held at the Westin St. Francis Hotel in San Francisco, - [INVESTIGATOR SPOTLIGHT](https://kidsfirstdrc.org/investigator-spotlight/) - Dr. Kenan Onel is an expert in cancer genetics and cancer biology. His research is aimed at identifying and studying the genetic basis of cancer susceptibility by identifying genes and genetic markers that alter cancer risk in both inherited and sporadic cancers. His work is largely directed towards developing studies minimizing inter-individual heterogeneity in order - [December 2022 – New Data Resources Available](https://kidsfirstdrc.org/december-2022-new-data-resources-available/) - New Data Resources Added to the Kids First Data Resource Portal The NIH Common Fund-supported Gabriella Miller Kids First Data Resource Center (Kids First DRC) is a dynamic and ever-growing effort to create opportunities for investigators across the research and healthcare landscape. It aims to connect researchers all over the world to collaborate and share resources toward - [Gabriella Miller Kids First DRC to Attend 2019 ASHG Annual Meeting](https://kidsfirstdrc.org/gabriella-miller-kids-first-drc-to-attend-2019-ashg-annual-meeting/) - The mission statement of the American Society for Human Genetics (ASHG) is "to advance human genetics and genomics in science, health, and society through excellence in research, education, and advocacy." In that effort, the organization works to propel research forward by creating opportunities for human genetics professionals to share research findings, clinical and research applications, and new - [Newest Developments at the Kids First DRC - July 2019](https://kidsfirstdrc.org/newest-developments-at-the-kids-first-drc-july-2019/) - The NIH Common Fund-supported Gabriella Miller Kids First Data Resource Center (Kids First DRC) is a dynamic and ever-growing effort to create opportunities for investigators, clinicians, patient families, foundations, and other stakeholders from across the research and healthcare landscape to collaborate and share resources toward a better understanding of the genetic causes and links between - [INVESTIGATOR SPOTLIGHT: Simeon Boyd, MD](https://kidsfirstdrc.org/investigator-spotlight-simeon-boyd-md/) - Dr. Simeon Boyadjiev Boyd is a pediatrician and board certified geneticist with extensive experience as a clinical and molecular dysmorphologist. He currently holds an appointment as a tenured professor in the Department of Pediatrics at the University of California, Davis. Between 2006 and 2011, he served as a founding chief of the Section of Genetics - [Creating New Opportunities for Collaboration and Discovery at the 2019 ASHG Annual Meeting](https://kidsfirstdrc.org/creating-new-opportunities-for-collaboration-and-discovery-at-the-2019-ashg-annual-meeting/) - TheAmerican Society of Human Genomics (ASHG) is the premiere professional membership organization for human genetics specialists worldwide, including nearly 8,000 members. Each year, the organization's Annual Meeting represents the largest gathering of human genetics experts in the world. The2019 ASHG Annual Meeting, held from October 15 to 19 at the George R. Brown Convention Center in - [Kids First DRC Investigators Engage the National Research Community to Share Insights on Global Collaboration and Data Sharing](https://kidsfirstdrc.org/kids-first-drc-investigators-engage-the-national-research-community-to-share-insights-on-global-collaboration-and-data-sharing/) - The NIH Common Fund-supported Gabriella Miller Kids First Pediatric Research Program (Kids First Program), and the Kids First Data Resource Center (Kids First DRC) are driven by a desire to maximize the availability and use of clinical and multi-omic data to further the understanding of the genetic causes of and links between childhood cancers and - [Updates at the Gabriella Miller Kids First Data Resource Center – October 2019](https://kidsfirstdrc.org/updates-at-the-gabriella-miller-kids-first-data-resource-center-october-2019/) - When the NIH Common Fund-supported Gabriella Miller Kids First Data Resource Center (Kids First DRC)'s Data Resource Portal first launched just over a year ago, it contained 30,000 files of data from 5,900 patients representing seven childhood cancer and structural birth defect datasets. Since then, the Data Resource Portal has undergone steady and significant growth - [Updates to the Kids First Data Resource Center - January 2020](https://kidsfirstdrc.org/updates-to-the-kids-first-data-resource-center-january-2020/) - Updates to the Gabriella Miller Kids First Data Resource Center - January 2020 The beginning of each new year invites time for measuring growth and milestones, for individuals as well as organizations and collaborating teams. The NIH Common Fund-supported Gabriella Miller Kids First Data Resource Center (Kids First DRC) has been pleased to observe significant - [Developing Personalized Treatment for Kids With Cancer](https://kidsfirstdrc.org/developing-personalized-treatment-for-kids-with-cancer/) - article courtesy of the Australian Research Data Commons Childhood cancer kills more children than any other disease in Australia and tragically, every week three children and adolescents in Australia currently die because of cancer. Every child is different, every cancer is unique, and so treatment has to be tailored for each individual. To personalize medicine, - [Kids First Data Resource Center at the 2020 NIH Rare Disease Day](https://kidsfirstdrc.org/kids-first-data-resource-center-at-the-2020-nih-rare-disease-day/) - Presented by the National Center for Advancing Translational Sciences (NCATS) and Clinical Center, the National Institutes of Health (NIH) Rare Disease Day takes place each year at the end of February. With the goal of raising awareness amongst the general public and decision-makers about rare diseases and their impact on patients' lives, Rare Disease Day - [Updates to the Kids First Data Resource Center - April 2020](https://kidsfirstdrc.org/updates-to-the-kids-first-data-resource-center-april-2020/) - The NIH Common Fund-supported Gabriella Miller Kids First Data Resource Center (Kids First DRC) was born out of a desire to unite researchers across the country and the world through shared resources; to uncover key insights that could potentially lead to better treatments for children with cancer, structural birth defects, and other rare diseases the - [Innovation Across the Phenotypic Translational Divide - Webinar Recap](https://kidsfirstdrc.org/innovation-across-the-phenotypic-translational-divide-webinar-recap/) - * NOTE: This article has been edited for clarity, and comes courtesy of the Monarch Initiative's blog at https://medium.com/@MonarchInit By: Nicole Vasilevsky, Adam Resnick, Deanne Taylor, Allison Heath, Peter Robinson, Monica Munoz-Torres, Nomi Harris and Melissa Haendel Sharing data from children affected by pediatric cancer and structural birth defects with the clinical and research community can - [Kids First DRC Program Updates - August 2020](https://kidsfirstdrc.org/kids-first-drc-program-updates-august-2020/) - To consider the state of national and international collaboration, scientific research, and cloud-based access in the year 2020 is to marvel at the spirit of innovation, commitment to big goals, and ability to remain flexible that has been shown across the pediatric medical community. As this unique and challenging year continues on, scientists and clinicians, - [INVESTIGATOR SPOTLIGHT: Melissa Haendel, PhD](https://kidsfirstdrc.org/investigator-spotlight-melissa-haendel-phd/) - Melissa Haendel is the Director of the Center for Data to Health (CD2H) at Oregon Health & Science University, and the Director of Translational Data Science at Oregon State University. Dr. Haendel also co-founded the Monarch Initiative, an international consortium focused on integration of genotype-phenotype data to improve rare disease diagnosis and mechanism discovery. With - [INVESTIGATOR SPOTLIGHT: Nicole Vasilevsky, PhD](https://kidsfirstdrc.org/investigator-spotlight-nicole-vasilevsky-phd/) - Nicole Vasilevsky is the Lead Biocurator for the Translational and Integrative Sciences Lab at Oregon Health & Science University (OHSU) in Portland, Oregon. Her current research focuses on development and use of semantic technologies that help computers understand data to facilitate new knowledge discovery and promote scientific reproducibility. Her expertise is in biocuration, which entails - [The NIH Common Fund Data Ecosystem](https://kidsfirstdrc.org/the-nih-common-fund-data-ecosystem/) - The Common Fund supports a number of Data Coordinating Centers (DCCs), such as the Kids First Data Resource Center, that provide curated data derived from hundreds of studies and samples collected from thousands of human subjects. An incredible diversity of datatypes has been generated at the genomic, expression, proteomic, metagenomic, and imaging levels, and the - [Kids First DRC Program Updates - February 2021](https://kidsfirstdrc.org/kids-first-drc-program-updates-february-2021/) - At a recent panel discussion hosted live on Facebook by U.S. Congresswoman Jennifer Wexton, experts and advocates in pediatric rare disease came together to reflect on the impact of the Gabriella Miller Kids First Pediatric Research Program (Kids First program) and to look toward the future for cross-disease research and continued development of the Kids First program. Among the - [INVESTIGATOR SPOTLIGHT: Sarath Babu](https://kidsfirstdrc.org/investigator-spotlight-sarath-babu/) - Sarath Babu is a lead bioinformatician for the Center for Precision Medicine and Genomics (CPMG) at Columbia University. His work involves performing large-scale genomic analysis to identify the genetic causes behind congenital kidney defects. - [INVESTIGATOR SPOTLIGHT: Laura Egolf](https://kidsfirstdrc.org/investigator-spotlight-laura-egolf/) - Laura Egolf is a PhD candidate in Cancer Biology at the University of Pennsylvania. She is conducting research at the Children’s Hospital of Philadelphia with mentorship from Sharon Diskin, PhD, and John Maris, MD. She seeks to better understand the genetic basis for neuroblastoma by applying computational methods to genomic data. She focuses on structural - [The Gabriella Miller Kids First DRC Partners with the NIH INCLUDE Project to Share Latest Research Breakthroughs at the 2022 ASHG Annual Meeting](https://kidsfirstdrc.org/the-gabriella-miller-kids-first-drc-partners-with-the-nih-include-project-to-share-latest-research-breakthroughs-at-the-2022-ashg-annual-meeting/) - The Gabriella Miller Kids First DRC Partners with the NIH INCLUDE Project to Share Latest Research Breakthroughs at the 2022 ASHG Annual Meeting At the Annual Meeting of the American Society of Human Genetics (ASHG), the Kids First DRC partnered with the NIH’s INCLUDE (INvestigation of Co-occuring conditions across the Lifespan to Understand Down syndromE) Program to host a - [Cross-Species Phenotyping of Structural Birth Defects and Childhood Cancer to Inform Genetic Discovery](https://kidsfirstdrc.org/cross-species-phenotyping-of-structural-birth-defects-and-childhood-cancer-to-inform-genetic-discovery/) - The Gabriella Miller Kids First Data Resource Portal houses genomic and associated clinical and phenotypic data from a variety of childhood cancer and structural birth defects cohorts. A critical next step to uncovering the causes and shared pathways underlying these conditions relies on functional validation using model systems and related tools and databases. As a follow-up to - [INVESTIGATOR SPOTLIGHT: Julie Jurgens, PhD](https://kidsfirstdrc.org/investigator-spotlight-julie-jurgens-phd/) - Dr. Jurgens is a Postdoctoral Research Fellow at Boston Children’s Hospital, where she studies the genetic basis of disorders of brain development in the laboratory of Dr. Elizabeth Engle. Dr. Jurgens obtained her undergraduate degree in Molecular and Cell Biology from the University of Illinois at Urbana-Champaign in 2010, where she researched mechanisms of learning - [INVESTIGATOR SPOTLIGHT: Arthur Lee, MD, PhD](https://kidsfirstdrc.org/investigator-spotlight-arthur-lee-md-phd/) - Arthur Lee MD, PhD is a postdoctoral fellow in the laboratory of Dr. Elizabeth Engle at Boston Children’s Hospital. He leverages next-generation sequencing technologies to identify the coding and non-coding genetic causes of the CCDDs, a set of rare pediatric disorders that affect movement of the eyes and face. Dr. Lee received his AB - [Kids First DRC Program Updates - Summer 2021](https://kidsfirstdrc.org/kids-first-drc-program-updates-summer-2021/) - The NIH Common Fund-supported Gabriella Miller Kids First Data Resource Center (Kids First DRC) has grown and evolved tremendously since its launch nearly three years ago. What began as a collection of 7 studies encompassing data from a little over 5,000 research participants has since grown to a collection of 23 datasets derived from over - [The Kids First Long-Read Sequencing Pilot Program: Applying New Technologies in Studying Childhood Cancer and Structural Birth Defects](https://kidsfirstdrc.org/the-kids-first-long-read-sequencing-pilot-program-applying-new-technologies-in-studying-childhood-cancer-and-structural-birth-defects/) - Contributed By: Kiran Garimella, DPhil; Broad Institute Shawn Levy, PhD; HudsonAlpha Institute for Biotechnology The human genome is complex, and very big. According to the National Human Genome Research Institute, a single chromosome can range in size from 50 to 300 million base pairs (DNA molecules, always paired together as A-T or C-G, that form two twisting - [INVESTIGATOR SPOTLIGHT: Eric Bogenschutz, PhD](https://kidsfirstdrc.org/investigator-spotlight-eric-bogenschutz-phd/) - Dr. Eric Bogenschutz is a Postdoctoral Associate studying the genetics of congenital diaphragmatic hernia (CDH) in Dr. Steve Murray’s group at The Jackson Laboratory. He obtained his undergraduate degree in Bioengineering from Montana State University in 2014, studying the diverse population of microbes that can survive in the extreme temperatures within the hot springs found - [INVESTIGATOR SPOTLIGHT: Michael Schatz, PhD](https://kidsfirstdrc.org/investigator-spotlight-michael-schatz-phd/) - Michael Schatz, Bloomberg Distinguished Associate Professor of Computer Science and Biology at Johns Hopkins University, is among the world’s foremost experts in solving computational problems in genomics research. His innovative biotechnologies and computational tools to study the sequence and function of genomes are advancing the understanding of the structure, evolution, and function of genomes for - [INVESTIGATOR SPOTLIGHT: Jamie E. Flerlage, MD, MS](https://kidsfirstdrc.org/investigator-spotlight-jamie-e-flerlage-md-ms/) - Pediatrician and pediatric hematologist/oncologist, Jamie Flerlage MD, came to St. Jude in 2012 to complete a three-year pediatric hematology/oncology fellowship and she never left. Today she is an assistant member of the Oncology Department faculty where she specializes in the investigation and treatment of Hodgkin lymphoma, a cancer of the lymphatic system, which makes and - [INVESTIGATOR SPOTLIGHT: Stephen R. Piccolo, PhD](https://kidsfirstdrc.org/investigator-spotlight-stephen-r-piccolo-phd/) - Stephen R. Piccolo is an associate professor in the Department of Biology at Brigham Young University (BYU). He earned a B.S. degree in Management Information Systems from BYU in 2001 and then worked as a software engineer for five years at Intel Corporation in Chandler, Arizona. In 2011, he received a PhD in Biomedical Informatics - [Kids First DRC Program Updates - October 2021](https://kidsfirstdrc.org/kids-first-drc-program-updates-october-2021/) - Updates to the Kids First Data Resource Center - Fall 2021 Now in its fourth year, the NIH Common Fund-supported Gabriella Miller Kids First Data Resource Center (Kids First DRC), is a leading resource and platform for the advancement of our fundamental understanding of pediatric cancers and structural birth defects. Recently surpassing 1.4PB of multi-omic - [INVESTIGATOR SPOTLIGHT: Jannine D. Cody, PhD](https://kidsfirstdrc.org/investigator-spotlight-jannine-d-cody-phd/) - Jannine De Mars Cody, PhD is currently a Professor of Genetics in the Department of Pediatrics at University of Texas Health San Antonio. In 1985 her daughter Elizabeth was born with a rare chromosome abnormality called 18q-. This was a condition that was easily diagnosed yet there was virtually no information on medical management or - [INVESTIGATOR SPOTLIGHT: Logan G. Spector, PhD](https://kidsfirstdrc.org/investigator-spotlight-logan-g-spector-phd/) - Dr. Spector is Professor of Pediatrics at the University of Minnesota and Suzanne Holmes Hodder Chair in Pediatric Cancer Research. He is immediate past Chair for Epidemiology with the Children’s Oncology Group and currently chair of the Childhood Cancer and Leukemia International Consortium (CLIC; www.clic.ngo). He also heads the Childhood Cancer Genomics Group at - [Gabriella Miller Kids First Data Resource Center Updates – December 2021](https://kidsfirstdrc.org/gabriella-miller-kids-first-data-resource-center-updates-december-2021/) - As many of us can report, it seems as though the past 12 months have passed by in a flash! 2021 was a year of great scientific progress, punctuated by COVID-19 related successes and setbacks, unprecedented levels of international data sharing, and renewed calls for open scientific collaboration from patient families and health advocates across - [Kids First Data Resource Center at ASHG 2021](https://kidsfirstdrc.org/kids-first-data-resource-center-at-ashg-2021/) - The American Society of Human Genomics (ASHG) is the premiere professional membership organization for human genetics specialists, with a member base of nearly 8,000 professionals worldwide. Each year an ASHG meeting is held to bring the experts of the field together to share emerging science, tools, and frameworks. The NIH Common Fund-supported Gabriella Miller Kids First Data Resource Center - [INVESTIGATOR SPOTLIGHT: Ian Krantz, MD](https://kidsfirstdrc.org/investigator-spotlight-ian-krantz-md/) - Dr. Krantz is a Pediatrician and Medical Geneticist. He is Director of the Roberts Individualized Medical Genetics Center (RIMGC), Director of the Center for Cornelia de Lange Syndrome and Related Diagnoses and PI on the Medical Genetics Training Grant (T32) at The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University - [INVESTIGATOR SPOTLIGHT: Bruce D. Gelb, PhD](https://kidsfirstdrc.org/investigator-spotlight-bruce-d-gelb-phd/) - Bruce D. Gelb, M.D. is the Director and Gogel Family Professor of the Mindich Child Health and Development Institute at the Icahn School of Medicine at Mount Sinai. He is Professor of Pediatrics and of Genetics and Genomic Sciences. Dr. Gelb completed a pediatric residency and pediatric cardiology fellowship at Babies Hospital of Columbia-Presbyterian Medical - [Rare Disease Day 2022](https://kidsfirstdrc.org/rare-disease-day-2022/) - Honoring Rare Disease Day through Patient Community Outreach Presented by the National Center for Advancing Translational Sciences (NCATS) and Clinical Center, the National Institutes of Health (NIH) Rare Disease Day shines a light on rare diseases, patients affected by them, and the current research happening across disciplines to find better therapies. Taking place every year at the - [Kids First DRC Program Updates - Spring 2022](https://kidsfirstdrc.org/kids-first-drc-program-updates-spring-2022/) - Updates at the Kids First Data Resource Center – Spring 2022 The Gabriella Miller Kids First Data Resource Center (Kids First DRC) is proud of the growth we have seen so far this year and we are excited to work towards more breakthroughs across the pediatric research field. As always, we are committed to supporting - [INVESTIGATOR SPOTLIGHT: Ariadne Letra, DDS, MS, PhD](https://kidsfirstdrc.org/ariadne-letra-dds-ms-phd/) - Dr. Letra is a dentist-scientist at the UTHealth School of Dentistry at Houston where she is a Professor of Diagnostic and Biomedical Sciences and member of the Center for Craniofacial Research. Her research laboratory focuses integrating large-scale phenotypic and genotypic data to facilitate understanding of the etiology of complex craniofacial traits such as cleft lip/palate, - [Investigator Spotlight: Philip J. Lupo, PhD, MPH](https://kidsfirstdrc.org/investigator-spotlight-philip-j-lupo-phd-mph/) - Dr. Philip Lupo is a genetic epidemiologist and Director of the Epidemiology and Population Sciences Program in the Texas Children’s Cancer and Hematology Center. A key area of his research is focused on cancer risk in children with birth defects. This work is facilitated through his involvement in the Children’s Oncology Group (COG), where - [Now Announcing Cloud Credit for All Researchers](https://kidsfirstdrc.org/now-announcing-cloud-credit-for-all-researchers/) - The NIH Common Fund’s Gabriella Miller Kids First Pediatric Research Program Offers Cloud Credit for All Researchers Analyzing large amounts of data require considerable computing ability and power. This is especially true when dealing with the rich data generated through childhood cancer and structural birth defects research. Historically, large-scale data analysis has required the use - [Upcoming Event: Accelerating Pediatric Genomics Research through Collaboration](https://kidsfirstdrc.org/upcoming-event-accelerating-pediatric-genomics-research-through-collaboration/) - The NIH Gabriella Miller Kids First Pediatric Research Program (Kids First) and INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) are hosting an ancillary poster session at the 2022 American Society of Human Genetics (ASHG) Annual Meeting in Los Angeles, CA on Tuesday, October 25 from 6:00pm-9:00pm at the JW Marriott Hotel. The Kids First and INCLUDE - [What I learned about the Kids First Program](https://kidsfirstdrc.org/what-i-learned-about-the-kids-first-program/) - This blog post comes courtesy of Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) As the program manager at the National Institutes of Health (NIH)-supported Gabriella Miller Kids First Pediatric Research Program (Kids First), a fun part of my job is to host webinars highlighting the program’s impact and resources. This month, - [Unlocking the Power of Pediatric Health Data: Insights from Kids First and INCLUDE](https://kidsfirstdrc.org/unlocking-the-power-of-pediatric-health-data-insights-from-kids-first-and-include/) - In the field of medical research, a vital collaboration between the National Institutes of Health (NIH) Common Fund’s Gabriella Miller Kids First Pediatric Research Program (Kids First) and the NIH INCLUDE Project is generating a novel dataset across pediatric conditions including Down syndrome (DS), leukemia, and heart defects, with a central mission to unveil the shared genetic pathways among - [Alex Hudson: Merging Science and Service at the Core of the Kids First Program](https://kidsfirstdrc.org/alex-hudson-merging-science-and-service-at-the-core-of-the-kids-first-program/) - Dr. Alex Hudson, the latest addition to the Kids First team, has joined the Kids First Program Team as a Presidential Management Fellow. Hailing from a distinguished background in academic excellence, a robust career in neuroscience research, and a profound commitment to public service, Alex shifted from a 14-year tenure in the laboratory toward a - [Kids First Fall Webinar Topic Was Collaboration and Genomic Research Across Pediatric Conditions](https://kidsfirstdrc.org/kids-first-fall-webinar-topic-was-collaboration-and-genomic-research-across-pediatric-conditions/) - The Kids First Fall Webinar gathered a diverse panel of speakers from Brazil, Argentina, and the US and an audience of 100+ attendees bringing researchers, clinicians, government, foundations, and patient families together. The topic of Collaborate to Accelerate Discoveries in Pediatric Research could not be more relevant. Collaboration for the Kids First program means developing a cloud resource and - [New Data Resources Added to the Kids First Data Resource Portal](https://kidsfirstdrc.org/new-data-resources-added-to-the-kids-first-data-resource-portal/) - The NIH Common Fund-supported Gabriella Miller Kids First Data Resource Center (Kids First DRC) is a dynamic and ever-growing effort to create opportunities for investigators across the research and healthcare landscape. It aims to connect researchers all over the world to collaborate and share resources toward a better understanding of the genetic causes and links between childhood ## Pages - [Home](https://kidsfirstdrc.org/) - THIS REPOSITORY IS UNDER REVIEW FOR POTENTIAL MODIFICATION IN COMPLIANCE WITH ADMINISTRATION DIRECTIVES View Portal See the Video Let’s Put Kids First in cancer and rare disease care. Drive Breakthroughs with collaborative data. Accelerating Cures for Kids First is our goal. FOR RESEARCHERS FOR FAMILIES Navigate to the next section THE VALUE OF KIDS FIRST - [Studies](https://kidsfirstdrc.org/studies/) - Kids First Studies Empower your research through Kids First data, tools and resources. Discover the robust collection of childhood cancer, congenital disorder, and cross-condition data available now. Learn more about these studies in the portal. Click here. - [Grants](https://kidsfirstdrc.org/grants/) - Big Support for Bold Ideas We’re Backing Brilliance: Accelerate Your Pediatric Research The Gabriella Miller Kids First Pediatric Research Program empowers determined investigators like you with the resources to unlock groundbreaking discoveries. Please check here for grant opportunities that can help shape a better understanding of rare childhood diseases. Navigate to the next section Kids First Cloud Credits - [What If](https://kidsfirstdrc.org/what-if/) - Play Video 1.25 files 150 samples 38 families 37 studies One child. One future. One chance to change everything. Learn Discover how Kids First is building the world’s largest collection of genetic and clinical data. Learn More Use Join thousands of scientists using Kids First data and analysis platforms to accelerate research. Use the Data - [Help Center](https://kidsfirstdrc.org/help-center/) - Welcome to the Kids First DRC Help Center! We are here to answer your questions. Get assistance accessing the data, learn alternative ways to support the project, or view frequently asked questions. - [Cost FAQs](https://kidsfirstdrc.org/help-center/cost-faqs/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security Cost FAQs Are there - [Data Security](https://kidsfirstdrc.org/help-center/security/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security How Kids First DRC - [Publications](https://kidsfirstdrc.org/publications/) - Search and filter Studies based on categories including, cancer, congenital anomalies and cross conditions. - [Be the Rare We Share](https://kidsfirstdrc.org/rare-we-share/) - Be the Rare We Share When conditions are rare, connection is everything. For too long, “rare” has implied isolated, unique, or alone. But within the Kids First Data Resource Center (Kids First DRC), we know a powerful truth: rare doesn’t mean alone. Robust Data Scientific Research Patients & Families Congenital disorder research works like a - [Events](https://kidsfirstdrc.org/events/) - [2025 Kids First / CAVATICA Data Migration Guide](https://kidsfirstdrc.org/help-center/2025-kids-first-cavatica-data-migration-guide/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security 2025 Kids First / - [Home old](https://kidsfirstdrc.org/home-old/) - The Kids First Data Resource Center (Kids First DRC) provides robust genetic and clinical data for pediatric cancer and congenital disorders. Kids First data is accessible to researchers worldwide, free of charge, to help us understand these diseases better. - [What If](https://kidsfirstdrc.org/whatif/) - 1.25 files 150 samples 38 families 37 studies One child. One future. One chance to change everything. Learn Discover how Kids First is building the world’s largest collection of genetic and clinical data. Learn More Use Join thousands of scientists using Kids First data and analysis platforms to accelerate research. Use the Data Support Join - [Let’s Turn Data Into Discovery Together](https://kidsfirstdrc.org/complete-profile/) - Let’s Turn Data Into Discovery Together Help us connect you with the updates that matter most. Name(Required) First Last Email(Required) RoleResearcherClinicianFamily MemberFoundationGovernmentOtherTitleInstitutionTopics of Interest Kids First DRC & Program Kids First Portal Updates NIH Program Funding & Support Childhood Cancer Research Congenital Disorders Research Cross-Disease Research Publications & Research Highlights Funding & Collaboration Opportunities (grants, - [ASHG2025](https://kidsfirstdrc.org/ashg2025/) - GET WICKED SMAAHT WITH KIDS FIRST AT ASHG 2025 Get the inside scoop on pediatric genomic data from the Gabriella Miller Kids First Data Resource Center (Kids First DRC)—and grab your own Professor Poppy.* She's an earnest educator who’s reminding researchers that wicked smaaht minds put Kids First. FIND OUT HOW AT BOOTH #1448 Smart - [2025 Kids First Data Migration Guide](https://kidsfirstdrc.org/help-center/data-migration-guide/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security 2025 Kids First Data - [10th Anniversary](https://kidsfirstdrc.org/10th-anniversary/) - A History of Dedication The Gabriella Miller Kids First Data Resource Center (Kids First DRC) is revolutionizing pediatric health research. What started as a bold vision has become a powerful collaboration among researchers, clinicians, and families, driving breakthroughs in childhood cancer and congenital disorders. As we celebrate 10 years, we honor a shared journey built on - [Community](https://kidsfirstdrc.org/community/) - Patient foundation advocates play a critical role in supporting the work of the Kids First Data Resource Center through advocacy and outreach efforts, promoting researcher enrollment, and informing others about the value of Kids First in driving progress toward more effective treatments and cures of childhood cancer and congenital conditions. - [FAQs](https://kidsfirstdrc.org/faqs/) - Frequently asked questions about the Kids First Data Resource Center and how the program works to support research into cancer and rare disease in children. - [Quick Start Guide](https://kidsfirstdrc.org/help-center/quick-start-guide/) - Welcome to the Kids First Data Resource Portal! We are excited to support you in our ongoing mission to discover insights into the biology of pediatric cancers and structural birth defects. - [From Day One to Publication](https://kidsfirstdrc.org/help-center/from-day-one-to-publication/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security From Day One to - [Video Tutorials](https://kidsfirstdrc.org/help-center/video-tutorials/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security Video Tutorials Play Video - [Cloud Credits](https://kidsfirstdrc.org/cloud-credits/) - Big Support for Bold Ideas We’re Backing Brilliance: Accelerate Your Pediatric Research The Gabriella Miller Kids First Pediatric Research Program empowers determined investigators like you with the resources to unlock groundbreaking discoveries. Please check here for support opportunities that can help shape a better understanding of rare childhood diseases. Navigate to the next section Kids First Cloud Credits - [Portal Tour](https://kidsfirstdrc.org/portal-tour/) - Discover Hope. Find Connection. Empower Change. Understanding a problem is the first step to solving it. Gabriella Miller Kids First Data Resource Center has created a robust research ecosystem to explore various pediatric conditions that researchers and physicians are investigating to find better treatments and cures. These tools are being leveraged across the entire pediatric - [AACR 2025](https://kidsfirstdrc.org/aacr-2025/) - Put Kids First in Cancer ResearchJoin us at the AACR Annual Meeting 2025. McCormick Place Convention CenterChicago, IL 25th-30th APRIL, 2025 Catch Kids First live in Chicago Attending the annual American Association of Cancer Research® (AACR) Annual Meeting 2025? Explore the robust data and powerful data, tools, and resources available through the Gabriella Miller Kids - [Resources](https://kidsfirstdrc.org/resources/) - Kids First studies on the portal are ready for analysis, having been harmonized and curated by the Kids First Data Resource Center team. These experts apply deep experience with pediatric data and are considerate of community feedback. Kids First data is functionally equivalent to other extensive genomic efforts such as GTeX and NCI Genomic Data Commons. - [Our Data Process](https://kidsfirstdrc.org/help-center/our-data-process/) - The role of the Kids First Data Resource Center is to harmonize these two types of data from two different sources into one, useable dataset. These datasets are first released to the original research groups; six months later they are released to the broader scientific community. - [ASHG2024](https://kidsfirstdrc.org/ashg2024/) - REACH NEW HEIGHTS! Help elevate pediatric cancer and rare disease research and take Poppy home. FIND OUT HOW AT BOOTH #1120 at the NIH Pavilion Attending the 2024 ASHG Annual Meeting? Put the Gabriella Miller Kids First Data Resource Center (Kids First DRC) on your map. Come out and prospect with Kids First spokes-goat Poppy. - [Variant Workbench](https://kidsfirstdrc.org/help-center/variant-workbench/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security Kids First Variant Workbench - [CFDE Pediatric PowerUp](https://kidsfirstdrc.org/powerup/) - Kids First CFDE PowerUpSupercharge Your Research Like a ProReady to blast off big data analysis? This summer, join the Pediatric PowerUp training program underwritten by the NIH Common Fund Data Ecosystem (CFDE) and featuring the Gabriella Miller Kids First Data Resource Center (Kids First). Dive into powerful cloud-based platforms that equip you with the skills - [Tools](https://kidsfirstdrc.org/tools/) - Getting Started is as Easy as 1-2-3. Use the Kids First Portal for searching and exploration, CAVATICA by Velsera for bioinformatic analysis, and PedcBioPortal for cancer-focused somatic discoveries. - [About](https://kidsfirstdrc.org/about/) - The Gabriella Miller Kids First Data Resource Center (Kids First DRC) is a collaborative pediatric research effort with the goal to understand the genetic causes and links between childhood cancer and congenital disorders. - [Poppy](https://kidsfirstdrc.org/poppy/) - WE'RE NOT KIDDING!Help accelerate pediatric cancer research and take Poppy home. Find out how at booth #3759 Looking for the cutest thing in San Diego? Attending the annual American Association of Cancer Research® (AACR) Annual Meeting 2024? Discover the Gabriella Miller Kids First Data Resource Center (Kids First DRC). Sign up for a demo to - [Applying for Cloud Credits](https://kidsfirstdrc.org/help-center/applying-for-cloud-credits/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security Applying for Cloud Credits - [Export Locally](https://kidsfirstdrc.org/help-center/export-locally/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security Export Locally The Kids - [Cavatica Cloud Platform](https://kidsfirstdrc.org/help-center/cavatica-cloud-platform/) - CAVATICA is a data analysis and sharing platform designed to accelerate discovery in a scalable, cloud-based compute environment where data, results, and workflows are shared among the world’s research community. - [Data Dictionary](https://kidsfirstdrc.org/help-center/data-dictionary/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security Portal Data Dictionary Data - [Variant Search](https://kidsfirstdrc.org/help-center/variant-search/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security Variant Search Just as - [Data Files Tab](https://kidsfirstdrc.org/help-center/data-files-tab/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security Data Files Tab Data - [Biospecimens Tab](https://kidsfirstdrc.org/help-center/biospecimens-tab/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security Biospecimens Tab Biospecimens in - [Participants Tab](https://kidsfirstdrc.org/help-center/participants-tab/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security Participants Tab Participants in - [Applying Filters](https://kidsfirstdrc.org/help-center/applying-filters/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security Applying Filters The Data - [Connecting Platforms](https://kidsfirstdrc.org/help-center/connecting-platforms/) - Users requesting access to controlled data are required to have an eRA Commons account. While most dataset access within the Kids First Portal is granted through dbGaP, there are some datasets whose access is reviewed and granted through consortia Data Access Committees (DACs). - [Accessing Controlled Data via dbGaP](https://kidsfirstdrc.org/help-center/accessing-controlled-data-via-dbgap/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security Accessing Controlled Data via - [Studies Tool](https://kidsfirstdrc.org/help-center/studies-tool/) - Getting StartedQuick Start Guide Video Tutorials Studies Tool Our Data Process Accessing Controlled Data via dbGaP Connecting Platforms User Support Data ExplorationApplying Filters Participants Tab Biospecimens Tab Data Files Tab Variant Search Portal Data Dictionary Analyzing DataCavatica Cloud Platform Variant Workbench Export Locally Applying for Cloud Credits Cost FAQs Data Security Studies Tool The Studies - [Policies](https://kidsfirstdrc.org/policies/) - Disclaimer of Endorsement Last Update Date: 07/13/18 The Kids First Data Resource Center (“DRC”) comprises partnered institutions supported by the NIH Common Fund under Award Number U2CHL138346 as part of the Common Fund’s Gabriella Miller Kids First Pediatric Research Program (“Kids First”). All content, terms and conditions and policies associated with the DRC Portal and ## Events - [Kids First Spring Public Webinar](https://kidsfirstdrc.org/event/kids-first-spring-public-webinar/) - Catch the next wave of scientific progress for children at the Kids First Spring Public Webinar: Ride the Wave of Discovery. Join us on May 13, 2026, for the Kids First Spring Public Webinar, where researchers, clinicians, and data scientists explore how shared data and advanced tools are accelerating discoveries across childhood cancers and congenital - [AACR Pediatrics](https://kidsfirstdrc.org/event/aacr-pediatrics/) - Website: https://www.aacr.org/meeting/aacr-conference-on-pancreatic-cancer/ Organizer American Association for Cancer Research - [MasterClass - Live Mentorship for Advanced Users](https://kidsfirstdrc.org/event/masterclass-live-mentorship-for-advanced-users/) - Already working with Kids First data? Join us for a deeper dive into common mid-project questions, optimization strategies, and Q&A with experts. Troubleshoot in real time Explore advanced tools Get unstuck and move forward Third Thursday of the Month | 2 p.m. ET - [SupportU - Interactive Learning for New Users](https://kidsfirstdrc.org/event/supportu/) - Just getting started with Kids First? We’ll walk you through everything — from portal basics to analysis tools — in a friendly, interactive session designed for new users. Interactive Learning for New Users Ecosystem overview How to access data Tools to get started First Tuesday of the Month | 10 a.m. ET - [American Society of Human Genetics 2026](https://kidsfirstdrc.org/event/american-society-of-human-genetics-2026/) - Showcase your research, connect with leaders in human genetics and genomics, and contribute to the scientific program. - [14th Structural Birth Defects Meeting](https://kidsfirstdrc.org/event/14th-structural-birth-defects-meeting/) - Organizer Society for Developmental Biology Website: https://www.sdbonline.org/meeting?ResourceID=4507 - [Fall Public Webinar](https://kidsfirstdrc.org/event/fall-public-webinar/) - Organizer Gabriella Miller Kids First Pediatric Research Program - [Community Webinar](https://kidsfirstdrc.org/event/community-webinar/) - Organizer Gabriella Miller Kids First Pediatric Research Program - [Rare Disease Day](https://kidsfirstdrc.org/event/rare-disease-day/) - Organizer Gabriella Miller Kids First Pediatric Research Program Venue Washington, DC ## Publications - [An evaluation of genetic predisposition to congenital anomalies and pediatric cancer supports KAT6B as a novel neuroblastoma susceptibility gene](https://kidsfirstdrc.org/publication/an-evaluation-of-genetic-predisposition-to-congenital-anomalies-and-pediatric-cancer-supports-kat6b-as-a-novel-neuroblastoma-susceptibility-gene/) - Purpose: Although congenital anomalies are among the strongest risk factors for developing pediatric cancer, the genetic underpinnings remain unclear. Therefore, we evaluated germline susceptibility in children with congenital anomalies and cancer. Methods: Through the Genetic Overlap Between Anomalies and Cancer in Kids Study, we recruited 47 participants with anomalies and cancer, along with their biological - [Personas for the translational workforce](https://kidsfirstdrc.org/publication/personas-for-the-translational-workforce/) - Twelve evidence-based profiles of roles across the translational workforce and two patients were made available through clinical and translational science (CTS) Personas, a project of the Clinical and Translational Science Awards (CTSA) Program National Center for Data to Health (CD2H). The persona profiles were designed and researched to demonstrate the key responsibilities, motivators, goals, software - [Data Lakes, Clouds, and Commons: A Review of Platforms for Analyzing and Sharing Genomic Data](https://kidsfirstdrc.org/publication/data-lakes-clouds-and-commons-a-review-of-platforms-for-analyzing-and-sharing-genomic-data/) - Data commons collate data with cloud computing infrastructure and commonly used software services, tools, and applications to create biomedical resources for the large-scale management, analysis, harmonization, and sharing of biomedical data. Over the past few years, data commons have been used to analyze, harmonize, and share large-scale genomics datasets. Data ecosystems can be built by - [Role of repulsive guidance signaling and GPR180 in pediatric low-grade glioma infiltration](https://kidsfirstdrc.org/publication/role-of-repulsive-guidance-signaling-and-gpr180-in-pediatric-low-grade-glioma-infiltration/) - Pediatric low-grade gliomas (pLGGs) are the most common brain tumors in children with varying degrees of infiltration. Despite having a positive prognosis, if the standard treatment, gross total resection, is impossible due to tumor location or diffuseness, outcomes worsen. Development of targeted therapeutics for diverse subtypes of pLGGs is limited by a lack of genetic - [A Framework for the Interoperability of Cloud Platforms: Towards FAIR Data in SAFE Environments](https://kidsfirstdrc.org/publication/a-framework-for-the-interoperability-of-cloud-platforms-towards-fair-data-in-safe-environments/) - As the number of cloud platforms supporting scientific research grows, there is an increasing need to support interoperability between two or more cloud platforms. A well accepted core concept is to make data in cloud platforms Findable, Accessible, Interoperable and Reusable (FAIR). We introduce a companion concept that applies to cloud-based computing environments that we - [Expanding the MOG phenotype: Brainstem encephalitis with punctate and curvilinear enhancement](https://kidsfirstdrc.org/publication/expanding-the-mog-phenotype-brainstem-encephalitis-with-punctate-and-curvilinear-enhancement/) - Myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated demyelination has been associated with a range of clinical phenotypes, including acute disseminated encephalomyelitis (ADEM), ADEM followed by recurrent optic neuritis, aquaporin 4–negative neuromyelitis optica spectrum disorder, and less commonly, brainstem encephalitis.1 In contrast, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a clinical, radiologic, and - [Alternative lengthening of telomeres (ALT) in pediatric high-grade gliomas can occur without ATRX mutation and is enriched in patients with pathogenic germline mismatch repair (MMR) variants](https://kidsfirstdrc.org/publication/alternative-lengthening-of-telomeres-alt-in-pediatric-high-grade-gliomas-can-occur-without-atrx-mutation-and-is-enriched-in-patients-with-pathogenic-germline-mismatch-repair-mmr-variants/) - Background: To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available. Methods: We performed C-circle analysis (CCA) on 579 pediatric brain - [FAT4 identified as a potential modifier of orofacial cleft laterality](https://kidsfirstdrc.org/publication/fat4-identified-as-a-potential-modifier-of-orofacial-cleft-laterality/) - Orofacial clefts (OFCs) are common (1 in 700 births) congenital malformations that include a cleft lip (CL) and cleft lip and palate (CLP). These OFC subtypes are also heterogeneous themselves, with the CL occurring on the left, right, or both sides of the upper lip. Unilateral CL and CLP have a 2:1 bias towards left-sided - [Integrative approaches generate insights into the architecture of non-syndromic cleft lip with or without cleft palate](https://kidsfirstdrc.org/publication/integrative-approaches-generate-insights-into-the-architecture-of-non-syndromic-cleft-lip-with-or-without-cleft-palate/) - Non-syndromic cleft lip with or without cleft palate (nsCL/P) is a common congenital facial malformation with a multifactorial etiology. Genome-wide association studies (GWASs) have identified multiple genetic risk loci. However, functional interpretation of these loci is hampered by the underrepresentation in public resources of systematic functional maps representative of human embryonic facial development. To generate - [EM-mosaic detects mosaic point mutations that contribute to congenital heart disease](https://kidsfirstdrc.org/publication/em-mosaic-detects-mosaic-point-mutations-that-contribute-to-congenital-heart-disease/) - Background: The contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined. Methods: We developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived - [X-linked genetic associations in sporadic thoracic aortic dissection](https://kidsfirstdrc.org/publication/x-linked-genetic-associations-in-sporadic-thoracic-aortic-dissection/) - The male predominance in sporadic thoracic aortic aneurysm and dissection (TAD) suggests that the X chromosome contributes to TAD, but this has not been tested. We investigated whether X-linked variation-common (minor allele frequency [MAF] ≥0.01) and rare (MAF - [Synergistic Associations of PNPLA3 I148M Variant, Alcohol Intake, and Obesity With Risk of Cirrhosis, Hepatocellular Carcinoma, and Mortality](https://kidsfirstdrc.org/publication/synergistic-associations-of-pnpla3-i148m-variant-alcohol-intake-and-obesity-with-risk-of-cirrhosis-hepatocellular-carcinoma-and-mortality/) - Importance: Alcohol drinking and obesity are associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC), but the risk is not uniform among people with these risk factors. Genetic variants, such as I148M in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, may play an important role in modulating cirrhosis and HCC risk. Objective: - [Dexamethasone Suppresses Palatal Cell Proliferation through miR-130a-3p](https://kidsfirstdrc.org/publication/dexamethasone-suppresses-palatal-cell-proliferation-through-mir-130a-3p/) - Cleft lip with or without cleft palate (CL/P) is one of the most common congenital birth defects. This study aims to identify novel pathogenic microRNAs associated with cleft palate (CP). Through data analyses of miRNA-sequencing for developing palatal shelves of C57BL/6J mice, we found that miR-449a-3p, miR-449a-5p, miR-449b, miR-449c-3p, and miR-449c-5p were significantly upregulated, and - [Maternal effect genes: Update and review of evidence for a link with birth defects](https://kidsfirstdrc.org/publication/maternal-effect-genes-update-and-review-of-evidence-for-a-link-with-birth-defects/) - Maternal effect genes (MEGs) encode factors (e.g., RNA) that are present in the oocyte and required for early embryonic development. Hence, while these genes and gene products are of maternal origin, their phenotypic consequences result from effects on the embryo. The first mammalian MEGs were identified in the mouse in 2000 and were associated with - [muCNV: Genotyping Structural Variants for Population-level Sequencing](https://kidsfirstdrc.org/publication/mucnv-genotyping-structural-variants-for-population-level-sequencing/) - Motivation: There are high demands for joint genotyping of structural variations with short-read sequencing, but efficient and accurate genotyping in population scale is a challenging task. Results: We developed muCNV that aggregates per-sample summary pileups for joint genotyping of > 100,000 samples. Pilot results show very low Mendelian inconsistencies. Applications to large-scale projects in cloud - [MicroRNA-124-3p suppresses mouse lip mesenchymal cell proliferation through the regulation of genes associated with cleft lip in the mouse](https://kidsfirstdrc.org/publication/microrna-124-3p-suppresses-mouse-lip-mesenchymal-cell-proliferation-through-the-regulation-of-genes-associated-with-cleft-lip-in-the-mouse/) - Background: Cleft lip (CL), one of the most common congenital birth defects, shows considerable geographic and ethnic variation, with contribution of both genetic and environmental factors. Mouse genetic studies have identified several CL-associated genes. However, it remains elusive how these CL-associated genes are regulated and involved in CL. Environmental factors may regulate these genes at - [High-coverage whole-genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios](https://kidsfirstdrc.org/publication/high-coverage-whole-genome-sequencing-of-the-expanded-1000-genomes-project-cohort-including-602-trios/) - The 1000 Genomes Project (1kGP) is the largest fully open resource of whole-genome sequencing (WGS) data consented for public distribution without access or use restrictions. The final, phase 3 release of the 1kGP included 2,504 unrelated samples from 26 populations and was based primarily on low-coverage WGS. Here, we present a high-coverage 3,202-sample WGS 1kGP - [Meerkat: An Algorithm to Reliably Identify Structural Variations and Predict Their Forming Mechanisms](https://kidsfirstdrc.org/publication/meerkat-an-algorithm-to-reliably-identify-structural-variations-and-predict-their-forming-mechanisms/) - Next-generation sequencing technologies have been widely used to query genetic variants in normal individuals as well as in those with diseases. Large-scale structural variations are a common source of genetic diversity in human population, and some of them have significant contributions to the etiology of diseases. However, the detection of large-scale structural variations from sequencing - [DMRscaler: a scale-aware method to identify regions of differential DNA methylation spanning basepair to multi-megabase features](https://kidsfirstdrc.org/publication/dmrscaler-a-scale-aware-method-to-identify-regions-of-differential-dna-methylation-spanning-basepair-to-multi-megabase-features/) - Background: Pathogenic mutations in genes that control chromatin function have been implicated in rare genetic syndromes. These chromatin modifiers exhibit extraordinary diversity in the scale of the epigenetic changes they affect, from single basepair modifications by DNMT1 to whole genome structural changes by PRM1/2. Patterns of DNA methylation are related to a diverse set of - [Balancing the transcriptome: leveraging sample similarity to improve measures of gene specificity](https://kidsfirstdrc.org/publication/balancing-the-transcriptome-leveraging-sample-similarity-to-improve-measures-of-gene-specificity/) - The spatial and temporal domain of a gene's expression can range from ubiquitous to highly specific. Quantifying the degree to which this expression is unique to a specific tissue or developmental timepoint can provide insight into the etiology of genetic diseases. However, quantifying specificity remains challenging as measures of specificity are sensitive to similarity between - [Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms](https://kidsfirstdrc.org/publication/novel-variants-in-kat6b-spectrum-of-disorders-expand-our-knowledge-of-clinical-manifestations-and-molecular-mechanisms/) - The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and - [From chemoproteomic-detected amino acids to genomic coordinates: insights into precise multi-omic data integration](https://kidsfirstdrc.org/publication/from-chemoproteomic-detected-amino-acids-to-genomic-coordinates-insights-into-precise-multi-omic-data-integration/) - The integration of proteomic, transcriptomic, and genetic variant annotation data will improve our understanding of genotype-phenotype associations. Due, in part, to challenges associated with accurate inter-database mapping, such multi-omic studies have not extended to chemoproteomics, a method that measures the intrinsic reactivity and potential "druggability" of nucleophilic amino acid side chains. Here, we evaluated mapping - [Metabolic reprogramming and epigenetic changes of vital organs in SARS-CoV-2-induced systemic toxicity](https://kidsfirstdrc.org/publication/metabolic-reprogramming-and-epigenetic-changes-of-vital-organs-in-sars-cov-2-induced-systemic-toxicity/) - Extrapulmonary manifestations of COVID-19 are associated with a much higher mortality rate than pulmonary manifestations. However, little is known about the pathogenesis of systemic complications of COVID-19. Here, we create a murine model of SARS-CoV-2-induced severe systemic toxicity and multiorgan involvement by expressing the human ACE2 transgene in multiple tissues via viral delivery, followed by - [K-mer analysis of long-read alignment pileups for structural variant genotyping](https://kidsfirstdrc.org/publication/k-mer-analysis-of-long-read-alignment-pileups-for-structural-variant-genotyping/) - Accurately genotyping structural variant (SV) alleles is crucial to genomics research. We present a novel method (kanpig) for genotyping SVs that leverages variant graphs and k-mer vectors to rapidly generate accurate SV genotypes. Benchmarking against the latest SV datasets shows kanpig achieves a single-sample genotyping concordance of 82.1%, significantly outperforming existing tools, which average 66.3%. - [Transient mRNA CAR T cells targeting GD2 provide dose-adjusted efficacy against diffuse midline glioma and high-grade glioma models](https://kidsfirstdrc.org/publication/transient-mrna-car-t-cells-targeting-gd2-provide-dose-adjusted-efficacy-against-diffuse-midline-glioma-and-high-grade-glioma-models/) - Background: Diffuse midline glioma (DMG) and high-grade glioma are devastating pediatric central nervous system tumors that remain incurable. Recent chimeric antigen receptor (CAR) T cell studies have shown proof of concept and early signs of efficacy against DMG targeting GD2. Prior work and ongoing clinical trials have focused on using viral vectors to create permanent - [Benchmarking Transformer Embedding Models for Biomedical Terminology Standardization](https://kidsfirstdrc.org/publication/benchmarking-transformer-embedding-models-for-biomedical-terminology-standardization/) - Biomedical text in public databases often exhibits unstandardized terminology and inconsistencies that impede machine learning applications and hinder data integration across biomedical databases. Leveraging generalized and specialized transformer/large language models (LLMs) offers a potential scalable solution for terminology standardization. We evaluated this opportunity using the National Institutes of Health Clinical Trials Registry (CTR), which contains - [Genetic association analysis of 77,539 genomes reveals rare disease etiologies](https://kidsfirstdrc.org/publication/genetic-association-analysis-of-77539-genomes-reveals-rare-disease-etiologies-2/) - The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the 'Rareservoir', containing the rare variant genotypes and phenotypes of 77,539 participants - [Approaching complete genomes, transcriptomes and epi-omes with accurate long-read sequencing](https://kidsfirstdrc.org/publication/approaching-complete-genomes-transcriptomes-and-epi-omes-with-accurate-long-read-sequencing/) - The year 2022 will be remembered as the turning point for accurate long-read sequencing, which now establishes the gold standard for speed and accuracy at competitive costs. We discuss the key bioinformatics techniques needed to power long reads across application areas and close with our vision for long-read sequencing over the coming years. - [Co-occurrence of congenital anomalies and childhood brain tumors in 22 million live births](https://kidsfirstdrc.org/publication/co-occurrence-of-congenital-anomalies-and-childhood-brain-tumors-in-22-million-live-births/) - Children born with a congenital anomaly have a higher risk of developing a brain tumor during childhood or adolescence, but the co-occurrence between specific types of congenital anomalies and specific types of childhood brain tumors (CBTs) is not well described. This study characterized the associations between specific congenital anomalies and CBTs.We leveraged a population-based registry - [Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium](https://kidsfirstdrc.org/publication/nonchromosomal-birth-defects-and-risk-of-childhood-acute-leukemia-an-assessment-in-15-000-leukemia-cases-and-46-000-controls-from-the-childhood-cancer-and-leukemia-international-conso/) - Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies - [A multicenter observational cohort study in survivors of Down Syndrome-associated acute leukemia (ALTE22C1): a report from the Children's Oncology Group](https://kidsfirstdrc.org/publication/a-multicenter-observational-cohort-study-in-survivors-of-down-syndrome-associated-acute-leukemia-alte22c1-a-report-from-the-childrens-oncology-group/) - Down syndrome (DS) is a common genetic disorder resulting from an extra copy of genetic material from all or part of chromosome 21. Individuals with DS have a higher burden of co-occurring structural birth defects, neurocognitive delay, and chronic health conditions when compared to those without DS, as well as a 10 to 20-fold excess - [RNA editing regulates host immune response and T cell homeostasis in SARS-CoV-2 infection](https://kidsfirstdrc.org/publication/rna-editing-regulates-host-immune-response-and-t-cell-homeostasis-in-sars-cov-2-infection/) - Adenosine to inosine (A-to-I) RNA editing by ADAR1 has been implicated in maintaining self-tolerance, preventing autoimmunity, and mediating antiviral immunity. Foreign viral double-stranded RNA triggers rapid interferon response and activates ADAR1 in the host immune system. Emerging data points to a role of ADAR1 A-to-I editing in the inflammatory response associated with severe COVID-19 disease. - [Protocol for in vitro co-culture assay for rapid expansion of human T cell acute lymphoblastic leukemia](https://kidsfirstdrc.org/publication/protocol-for-in-vitro-co-culture-assay-for-rapid-expansion-of-human-t-cell-acute-lymphoblastic-leukemia/) - T cell acute lymphoblastic leukemia (T-ALL) is a rare but aggressive hematological cancer that occurs primarily in children and adolescents. Here, we present a protocol for in vitro co-culture assay that enables robust expansion of primary T-ALL cells. We describe steps for seeding T-ALL and stromal cells in 3D organoids and subsequent flow analysis to - [Malignant A-to-I RNA editing by ADAR1 drives T cell acute lymphoblastic leukemia relapse via attenuating dsRNA sensing](https://kidsfirstdrc.org/publication/malignant-a-to-i-rna-editing-by-adar1-drives-t-cell-acute-lymphoblastic-leukemia-relapse-via-attenuating-dsrna-sensing/) - Leukemia-initiating cells (LICs) are regarded as the origin of leukemia relapse and therapeutic resistance. Identifying direct stemness determinants that fuel LIC self-renewal is critical for developing targeted approaches. Here, we show that the RNA-editing enzyme ADAR1 is a crucial stemness factor that promotes LIC self-renewal by attenuating aberrant double-stranded RNA (dsRNA) sensing. Elevated adenosine-to-inosine editing - [bamSliceR: a Bioconductor package for rapid, cross-cohort variant and allelic bias analysis](https://kidsfirstdrc.org/publication/bamslicer-a-bioconductor-package-for-rapid-cross-cohort-variant-and-allelic-bias-analysis/) - Motivation: The National Cancer Institute Genomic Data Commons (GDC) provides controlled access to sequencing data from thousands of subjects, enabling large-scale study of impactful genetic alterations such as simple and complex germline and structural variants. However, efficient analysis requires significant computational resources and expertise, especially when calling variants from raw sequence reads. To solve these - [TRIM28-dependent developmental heterogeneity determines cancer susceptibility through distinct epigenetic states](https://kidsfirstdrc.org/publication/trim28-dependent-developmental-heterogeneity-determines-cancer-susceptibility-through-distinct-epigenetic-states/) - Mutations in cancer risk genes increase susceptibility, but not all carriers develop cancer. Indeed, while DNA mutations are necessary drivers of cancer, only a small subset of mutated cells go on to cause the disease. To date, the mechanisms underlying individual cancer susceptibility remain unclear. Here, we took advantage of a unique mouse model of - [Whole-genome sequencing reveals individual and cohort level insights into chromosome 9p syndromes](https://kidsfirstdrc.org/publication/whole-genome-sequencing-reveals-individual-and-cohort-level-insights-into-chromosome-9p-syndromes/) - Background: Previous genomic efforts on chromosome 9p deletion and duplication syndromes have utilized low-resolution strategies (i.e., karyotypes, chromosome microarrays). These studies have provided important initial insights into these syndromes. This current study is the first large-scale whole-genome sequencing (WGS) study of 100 individuals from families with chromosome 9p syndromes. Methods: Through the newly formed 9P-ARCH - [Classification and risk stratification in T-lineage acute lymphoblastic leukemia](https://kidsfirstdrc.org/publication/classification-and-risk-stratification-in-t-lineage-acute-lymphoblastic-leukemia/) - Cure rates for patients with acute lymphoblastic leukemia (ALL) have improved markedly in recent decades, in part because of risk stratification incorporating leukemia genomics, response to treatment, and clinical features to be able to determine at diagnosis which patients are more likely to relapse or have refractory disease. Although risk stratification is well developed for - [Gain-of-function variants and overexpression of RUNX2 in patients with nonsyndromic midline craniosynostosis](https://kidsfirstdrc.org/publication/gain-of-function-variants-and-overexpression-of-runx2-in-patients-with-nonsyndromic-midline-craniosynostosis/) - Craniosynostosis (CS), the premature fusion of one or more cranial sutures, is a relatively common congenital anomaly, occurring in 3-5 per 10,000 live births. Nonsyndromic CS (NCS) accounts for up to 80% of all CS cases, yet the genetic factors contributing to the disorder remain largely unknown. The RUNX2 gene, encoding a transcription factor critical - [A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis](https://kidsfirstdrc.org/publication/a-genome-wide-association-study-implicates-the-bmp7-locus-as-a-risk-factor-for-nonsyndromic-metopic-craniosynostosis/) - Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10-8): rs781716 (P - [PERADIGM: Phenotype embedding similarity-based rare disease gene mapping](https://kidsfirstdrc.org/publication/peradigm-phenotype-embedding-similarity-based-rare-disease-gene-mapping/) - Identifying genes associated with rare diseases remains challenging due to the scarcity of patients and the limited statistical power of traditional association methods. Here, we introduce PERADIGM ( Phenotype Embedding similarity-based RAre DIsease Gene Mapping), a novel framework that leverages natural language processing techniques to integrate comprehensive phenotype information from electronic health records for rare - [Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes](https://kidsfirstdrc.org/publication/genomic-analysis-of-11555-probands-identifies-60-dominant-congenital-heart-disease-genes/) - Congenital heart disease (CHD) is a leading cause of infant mortality. We analyzed de novo mutations (DNMs) and very rare transmitted/unphased damaging variants in 248 prespecified genes in 11,555 CHD probands. The results identified 60 genes with a significant burden of heterozygous damaging variants. Variants in these genes accounted for CHD in 10.1% of probands - [Recessive genetic contribution to congenital heart disease in 5,424 probands](https://kidsfirstdrc.org/publication/recessive-genetic-contribution-to-congenital-heart-disease-in-5424-probands/) - Variants with large effect contribute to congenital heart disease (CHD). To date, recessive genotypes (RGs) have commonly been implicated through anecdotal ascertainment of consanguineous families and candidate gene-based analysis; the recessive contribution to the broad range of CHD phenotypes has been limited. We analyzed whole exome sequences of 5,424 CHD probands. Rare damaging RGs were - [Integrative modeling of transmitted and de novo variants identifies novel risk genes for congenital heart disease](https://kidsfirstdrc.org/publication/integrative-modeling-of-transmitted-and-de-novo-variants-identifies-novel-risk-genes-for-congenital-heart-disease/) - Background: Whole-exome sequencing (WES) studies have identified multiple genes enriched for de novo mutations (DNMs) in congenital heart disease (CHD) probands. However, risk gene identification based on DNMs alone remains statistically challenging due to heterogenous etiology of CHD and low mutation rate in each gene. Methods: In this manuscript, we introduce a hierarchical Bayesian framework - [Identification of neural crest and melanoma cancer cell invasion and migration genes using high-throughput screening and deep attention networks](https://kidsfirstdrc.org/publication/identification-of-neural-crest-and-melanoma-cancer-cell-invasion-and-migration-genes-using-high-throughput-screening-and-deep-attention-networks/) - Background: Cell migration and invasion are well-coordinated in development and disease but remain poorly understood. We previously showed that the neural crest (NC) cell migratory wavefront shares a 45-gene panel with other cell invasion phenomena. To rapidly and systematically identify critical genes, we performed a high-throughput siRNA screen and statistical and deep learning analyses to - [Challenges in the clinical understanding of genetic testing in birth defects and pediatric diseases](https://kidsfirstdrc.org/publication/challenges-in-the-clinical-understanding-of-genetic-testing-in-birth-defects-and-pediatric-diseases/) - Advances in prenatal/neonatal genetic screening practices and next generation sequencing (NGS) technologies have made the detection of molecular causes of pediatric diseases increasingly more affordable, accessible, and rapid in return of results. In the past, families searching for answers often required diagnostic journeys leading to delays in targeted care and missed diagnoses. Non-invasive prenatal NGS - [Rescuing lung development through embryonic inhibition of histone acetylation](https://kidsfirstdrc.org/publication/rescuing-lung-development-through-embryonic-inhibition-of-histone-acetylation/) - A major barrier to the impact of genomic diagnosis in patients with congenital malformations is the lack of understanding regarding how sequence variants contribute to disease pathogenesis and whether this information could be used to generate patient-specific therapies. Congenital diaphragmatic hernia (CDH) is among the most common and severe of all structural malformations; however, its - [MYT1 role in the microtia-craniofacial microsomia spectrum](https://kidsfirstdrc.org/publication/myt1-role-in-the-microtia-craniofacial-microsomia-spectrum/) - Craniofacial microsomia (CFM), also known as the oculo-auriculo-vertebral spectrum, comprises a variable phenotype with the most common features including microtia and mandibular hypoplasia on one or both sides, in addition to lateral oral clefts, epibulbar dermoids, cardiac, vertebral, and renal abnormalities. The etiology of CFM is largely unknown. The MYT1 gene has been reported as - [CTCF/RAD21 organize the ground state of chromatin-nuclear speckle association](https://kidsfirstdrc.org/publication/ctcf-rad21-organize-the-ground-state-of-chromatin-nuclear-speckle-association/) - Recent findings indicate that nuclear speckles, a distinct type of nuclear body, interact with certain chromatin regions in a ground state. Here, we report that the chromatin structural factors CTCF and cohesin are required for full ground-state association between DNA and nuclear speckles. We identified a putative speckle-targeting motif (STM) within cohesin subunit RAD21 and - [Emerging genomic biomarkers in diagnosis and classification of T-cell acute lymphoblastic leukemia](https://kidsfirstdrc.org/publication/emerging-genomic-biomarkers-in-diagnosis-and-classification-of-t-cell-acute-lymphoblastic-leukemia/) - Contemporary chemotherapy protocols have improved cure rates for children, adolescents, and young adults (CAYA) with T-lineage acute lymphoblastic leukemia (T-ALL) to greater than 80%. Unfortunately, outcomes for CAYA with relapsed and refractory disease, as well as older adults, remain poor. A key goal in the treatment of T-ALL therapy is preventing relapse; however, it is - [Native stem cell transcriptional circuits define cardinal features of high-risk leukemia](https://kidsfirstdrc.org/publication/native-stem-cell-transcriptional-circuits-define-cardinal-features-of-high-risk-leukemia/) - While the mutational landscape across early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) and ETP-like leukemia is known, establishing a unified framework that activates stem cell genes characteristic of these tumors remains elusive. Using complementary mouse and human models, chromatin mapping, and enhancer profiling, we show that the coactivator ZMIZ1 promotes normal and malignant ETP population - [High immunoproteasome and low constitutive proteasome subunit levels correlate with sensitivity to bortezomib-containing chemotherapy: update from the Children's Oncology Group AALL1231 trial](https://kidsfirstdrc.org/publication/high-immunoproteasome-and-low-constitutive-proteasome-subunit-levels-correlate-with-sensitivity-to-bortezomib-containing-chemotherapy-update-from-the-childrens-oncology-group-aall1231-trial/) - This correlative analysis from the Children’s Oncology Group AALL1231 trial suggests that bortezomib may benefit a biologically defined subset of newly diagnosed T-ALL patients rather than all-comers: leukemias with relatively high immunoproteasome and low constitutive proteasome subunit levels showed deeper early responses and better event-free survival when bortezomib was added to augmented BFM chemotherapy. In - [Riding the storm: managing cytokine-related toxicities in CAR-T cell therapy](https://kidsfirstdrc.org/publication/riding-the-storm-managing-cytokine-related-toxicities-in-car-t-cell-therapy/) - The advent of chimeric antigen receptor T cells (CAR-T) has been a paradigm shift in cancer immunotherapeutics, with remarkable outcomes reported for a growing catalog of malignancies. While CAR-T are highly effective in multiple diseases, salvaging patients who were considered incurable, they have unique toxicities which can be life-threatening. Understanding the biology and risk factors - [Autoimmune lymphoproliferative immunodeficiencies (ALPIDs): A proposed approach to redefining ALPS and other lymphoproliferative immune disorders](https://kidsfirstdrc.org/publication/autoimmune-lymphoproliferative-immunodeficiencies-alpids-a-proposed-approach-to-redefining-alps-and-other-lymphoproliferative-immune-disorders/) - Chronic nonmalignant lymphoproliferation and autoimmune cytopenia are relevant manifestations of immunohematologic diseases of childhood. Their diagnostic classification is challenging but important for therapy. Autoimmune lymphoproliferative syndrome (ALPS) is a genetically defined inborn error of immunity combining these manifestations, but it can explain only a small proportion of cases. Diagnostic categories such as ALPS-like disease, common - [Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction](https://kidsfirstdrc.org/publication/proteomic-profiling-of-mis-c-patients-indicates-heterogeneity-relating-to-interferon-gamma-dysregulation-and-vascular-endothelial-dysfunction/) - Multi-system Inflammatory Syndrome in Children (MIS-C) is a major complication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in pediatric patients. Weeks after an often mild or asymptomatic initial infection with SARS-CoV-2 children may present with a severe shock-like picture and marked inflammation. Children with MIS-C present with varying degrees of cardiovascular and hyperinflammatory - [Skewed Cytokine Responses Rather Than the Magnitude of the Cytokine Storm May Drive Cardiac Dysfunction in Multisystem Inflammatory Syndrome in Children](https://kidsfirstdrc.org/publication/skewed-cytokine-responses-rather-than-the-magnitude-of-the-cytokine-storm-may-drive-cardiac-dysfunction-in-multisystem-inflammatory-syndrome-in-children/) - Cardiac dysfunction is a prominent feature of multisystem inflammatory syndrome in children (MIS-C), yet the etiology is poorly understood. We determined whether dysfunction is global or regional, and whether it is associated with the cytokine milieu, microangiopathy, or severity of shock. Methods and Results We analyzed echocardiographic parameters of myocardial deformation and compared global and - [Optimizing therapy in the modern age: differences in length of maintenance therapy in acute lymphoblastic leukemia](https://kidsfirstdrc.org/publication/optimizing-therapy-in-the-modern-age-differences-in-length-of-maintenance-therapy-in-acute-lymphoblastic-leukemia/) - A majority of children and young adults with acute lymphoblastic leukemia (ALL) are cured with contemporary multiagent chemotherapy regimens. The high rate of survival is largely the result of 70 years of randomized clinical trials performed by international cooperative groups. Contemporary ALL therapy usually consists of cycles of multiagent chemotherapy administered over 2 to 3 - [Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations](https://kidsfirstdrc.org/publication/evidence-of-thrombotic-microangiopathy-in-children-with-sars-cov-2-across-the-spectrum-of-clinical-presentations/) - Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement - [Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2](https://kidsfirstdrc.org/publication/multisystem-inflammatory-syndrome-in-children-and-covid-19-are-distinct-presentations-of-sars-cov-2/) - Initial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide - [Convalescent plasma for pediatric patients with SARS-CoV-2-associated acute respiratory distress syndrome](https://kidsfirstdrc.org/publication/convalescent-plasma-for-pediatric-patients-with-sars-cov-2-associated-acute-respiratory-distress-syndrome/) - There are no proven safe and effective therapies for children who develop life-threatening complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Convalescent plasma (CP) has demonstrated potential benefit in adults with SARS-CoV-2, but has theoretical risks.We present the first report of CP in children with life-threatening coronavirus disease 2019 (COVID-19), providing data on four - [Sequencing Analysis Demonstrates That a Complex Genetic Architecture Contributes to Risk for Spina Bifida](https://kidsfirstdrc.org/publication/sequencing-analysis-demonstrates-that-a-complex-genetic-architecture-contributes-to-risk-for-spina-bifida/) - Spina bifida (SB), a common neural tube defects (NTDs), has a complex genetic architecture that remains incompletely understood. Although prior studies have identified rare, deleterious single nucleotide variants (SNVs) in SB, broader contributions to risk remain unclear. Here, we investigated shared genetic risk among 256 SB probands compared with 395 ancestry-matched controls using an unbiased - [TMEM161B modulates radial glial scaffolding in neocortical development](https://kidsfirstdrc.org/publication/tmem161b-modulates-radial-glial-scaffolding-in-neocortical-development/) - TMEM161B encodes an evolutionarily conserved widely expressed novel 8-pass transmembrane protein of unknown function in human. Here we identify TMEM161B homozygous hypomorphic missense variants in our recessive polymicrogyria (PMG) cohort. Patients carrying TMEM161B mutations exhibit striking neocortical PMG and intellectual disability. Tmem161b knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and - [Long-term Risk of Hypertension After Surgical Repair of Congenital Heart Disease in Children](https://kidsfirstdrc.org/publication/long-term-risk-of-hypertension-after-surgical-repair-of-congenital-heart-disease-in-children/) - The long-term risk of hypertension in children after surgery for congenital heart disease (CHD) is unclear.To assess the incidence of hypertension after cardiac surgery in children with CHD.A multicenter retrospective matched cohort study was conducted in Ontario, Canada, using administrative databases. A total of 3600 children with surgical repair of CHD were matched to 10 - [SoMaCX: a complex generative genome modeling framework](https://kidsfirstdrc.org/publication/somacx-a-complex-generative-genome-modeling-framework/) - Somatic structural variations (SVs) are commonly observed in cancer tissue, but remain challenging to discover with short and long read sequencing due to tumor heterogeneity and other technical sequencing factors. Only SVs with a sufficient fraction of reads spanning the event will be detectable, while issues like chromothripsis increase the complexity and resulting interpretation significantly. - [Heterozygous RAB3A variants cause cerebellar ataxia by a partial loss-of-function mechanism](https://kidsfirstdrc.org/publication/heterozygous-rab3a-variants-cause-cerebellar-ataxia-by-a-partial-loss-of-function-mechanism/) - RAB3A encodes a small GTP-binding protein that is abundant in brain synaptic vesicles and crucial for the release of neurotransmitters and synaptic plasticity. Here, we identified RAB3A as a candidate gene for autosomal dominant cerebellar ataxia by two independent approaches: linkage in a large dominant ataxia family and, in parallel, an untargeted computational genetic association - [Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy](https://kidsfirstdrc.org/publication/mutations-in-the-small-nuclear-rna-gene-rnu2-2-cause-a-severe-neurodevelopmental-disorder-with-prominent-epilepsy/) - The major spliceosome includes five small nuclear RNA (snRNAs), U1, U2, U4, U5 and U6, each of which is encoded by multiple genes. We recently showed that mutations in RNU4-2, the gene that encodes the U4-2 snRNA, cause one of the most prevalent monogenic neurodevelopmental disorders. Here, we report that recurrent germline mutations in RNU2-2 - [Unsupervised machine learning integrates genomic variants and EMR to unravel mechanisms of brain hemorrhage and epilepsy as early indicators of alzheimer's in down syndrome](https://kidsfirstdrc.org/publication/unsupervised-machine-learning-integrates-genomic-variants-and-emr-to-unravel-mechanisms-of-brain-hemorrhage-and-epilepsy-as-early-indicators-of-alzheimers-in-down-syndrome/) - No abstract available - [Deep learning algorithms reveal genomic markers for anxiety disorder in a large cohort of children with down syndrome](https://kidsfirstdrc.org/publication/deep-learning-algorithms-reveal-genomic-markers-for-anxiety-disorder-in-a-large-cohort-of-children-with-down-syndrome-2/) - Despite a significant burden of neurobehavioral and psychiatric comorbidities in children with Down syndrome (DS), and the general increased risk for anxiety in individuals with intellectual disabilities (ID), children with DS have significantly lower odds of anxiety. Understanding the specific mechanisms of anxiety in DS could inform the development of new treatments. This study performed - [Late effects after high-risk neuroblastoma (LEAHRN): a multicentre, cross-sectional cohort study from the Children's Oncology Group](https://kidsfirstdrc.org/publication/late-effects-after-high-risk-neuroblastoma-leahrn-a-multicentre-cross-sectional-cohort-study-from-the-childrens-oncology-group/) - Background: New treatment regimens have resulted in increasing numbers of children who survive high-risk neuroblastoma, but late effects of cancer therapy are not well studied. We aimed to explore treatment-related risk factors associated with late effects of modern therapies for high-risk neuroblastoma. Methods: This multicentre, cross-sectional cohort study of survivors of high-risk neuroblastoma was done at 88 - [Haploinsufficiency of GRHL2 is associated with orofacial clefting in humans](https://kidsfirstdrc.org/publication/haploinsufficiency-of-grhl2-is-associated-with-orofacial-clefting-in-humans/) - Orofacial clefts (OFCs) are one of the most common structural birth defects, with the prevalence of OFC varying across populations, and studies on the causes of OFCs in diverse populations are necessary, but still limited. We analyzed whole genome sequencing data on 419 parent-child trios from the Philippines, a population with a particularly high rate - [Germline pathogenic variation impacts somatic alterations and patient outcomes in pediatric central nervous system tumors](https://kidsfirstdrc.org/publication/germline-pathogenic-variation-impacts-somatic-alterations-and-patient-outcomes-in-pediatric-central-nervous-system-tumors/) - The contribution of rare pathogenic/likely pathogenic (P/LP) germline variants to pediatric central nervous system (CNS) tumor development remains understudied. Here, we characterize the prevalence and biological significance of germline P/LP variants in cancer predisposition genes across 830 CNS tumor patients from the Pediatric Brain Tumor Atlas (PBTA). We identify germline P/LP variants in 23.3% (193/830) - [Evaluating the Genetic Overlap Between Congenital Heart Disease and Neuroblastoma Risk](https://kidsfirstdrc.org/publication/evaluating-the-genetic-overlap-between-congenital-heart-disease-and-neuroblastoma-risk/) - Children with congenital heart disease (CHD) have elevated neuroblastoma (NB) risk, potentially due to shared neural crest origins. We analyzed rare exonic de novo single-nucleotide variants in 702 CHD and 454 NB trios from the Neuroblastoma Epidemiology in North America Study, Gabriella Miller Kids First Program, and a published cohort. Seven genes, including CHD risk - [Pharmacogenomics in Orofacial Clefts Care: Insights from Whole-Genome Sequencing of Case-Parents Trios](https://kidsfirstdrc.org/publication/pharmacogenomics-in-orofacial-clefts-care-insights-from-whole-genome-sequencing-of-case-parents-trios/) - Background/Objectives: Orofacial clefts (OFCs) are among the most common birth defects globally, sometimes exacerbated by adverse drug reactions (ADRs) from corticosteroids and antiepileptics. Comprehending the pharmacogenomic and pharmacogenetic elements that lead to ADRs is essential for enhancing precision medicine and clinical outcomes. This study examines rare genetic variants in drug-metabolizing and drug-transporting genes among Ghanaian - [Actomyosin contractility and a threshold of cadherin cell adhesion are required during tissue fusion](https://kidsfirstdrc.org/publication/actomyosin-contractility-and-a-threshold-of-cadherin-cell-adhesion-are-required-during-tissue-fusion/) - Tissue fusion is integral to mammalian morphogenesis, and its failure is a significant cause of structural anomalies, yet the underlying cellular mechanisms are incompletely understood. We examine cellular drivers of upper lip fusion in the mammalian embryo by establishing a live-imaging modality, revealing specific enrichment of F-actin that propagates in multicellular cables anchored at the - [Remodeling of the immune microenvironment is linked to adverse outcome in pediatric T cell acute lymphoblastic leukemia](https://kidsfirstdrc.org/publication/remodeling-of-the-immune-microenvironment-is-linked-to-adverse-outcome-in-pediatric-t-cell-acute-lymphoblastic-leukemia/) - Changes in the immune microenvironment are frequent in cancers occurring in adult patients, yet our understanding of the pediatric cancer immune microenvironment and its clinical relevance is limited. We investigate the immune microenvironment in pediatric T cell acute lymphoblastic leukemia (T-ALL), using single-cell CITE-seq and immune repertoire analyses. We identify a T-ALL subgroup characterized by - [A non-canonical lymphoblast in refractory childhood T-cell leukaemia](https://kidsfirstdrc.org/publication/a-non-canonical-lymphoblast-in-refractory-childhood-t-cell-leukaemia/) - Refractory cancers may arise either through the acquisition of resistance mechanisms or represent distinct disease states. The origin of childhood T-cell acute lymphoblastic leukaemia (T-ALL) that does not respond to initial treatment, i.e. refractory disease, is unknown. Refractory T-ALL carries a poor prognosis and cannot be predicted at diagnosis. Here, we perform single cell mRNA - [Dmxl1 is required for survival in the mouse to organogenesis stages of development](https://kidsfirstdrc.org/publication/dmxl1-is-required-for-survival-in-the-mouse-to-organogenesis-stages-of-development/) - Cleft lip and cleft palate are among the most common congenital anomalies and are the result of incomplete fusion of embryonic craniofacial processes or palatal shelves. Genetic factors are known to play a large role in these anomalies, but the list of known causal genes is far from complete. As part of a larger effort - [Improved identification of T-ALL paediatric patients with low MRD but poor prognosis using a transcriptional signature](https://kidsfirstdrc.org/publication/improved-identification-of-t-all-paediatric-patients-with-low-mrd-but-poor-prognosis-using-a-transcriptional-signature/) - No abstract available - [Sequencing validates deep learning models for EHR-based detection of Noonan syndrome in pediatric patients](https://kidsfirstdrc.org/publication/sequencing-validates-deep-learning-models-for-ehr-based-detection-of-noonan-syndrome-in-pediatric-patients/) - Despite advanced diagnostic tools, early detection of rare genetic conditions like Noonan syndrome (NS) remains challenging. We evaluated a deep learning model's real-world performance in identifying potential NS cases using electronic health record (EHR) data, validated through genetic sequencing and clinical assessment. The model analyzed 92,428 patients, identifying 171 high-risk individuals (score > 0.8) who - [Inferring chromosome segregation error stage and crossover in trisomic disorders with application to Down syndrome](https://kidsfirstdrc.org/publication/inferring-chromosome-segregation-error-stage-and-crossover-in-trisomic-disorders-with-application-to-down-syndrome/) - Errors in chromosome segregation during gametogenesis, such as nondisjunction (NDJ) errors, have severe consequences in human reproduction, and a better understanding of their etiology is of fundamental interest in genetics. Mapping NDJ errors to meiotic/mitotic stages typically requires proband-parent comparison, limiting its applicability. Herein, we develop Mis-segregation Error Identification through Hidden Markov Models (MeiHMM), a - [The Open Pediatric Cancer Project](https://kidsfirstdrc.org/publication/the-open-pediatric-cancer-project/) - Background: In 2019, the Open Pediatric Brain Tumor Atlas (OpenPBTA) was created as a global, collaborative open-science initiative to genomically characterize 1,074 pediatric brain tumors and 22 patient-derived cell lines. Here, we present an extension of the OpenPBTA called the Open Pediatric Cancer (OpenPedCan) Project, a harmonized open-source multiomic dataset from 6,112 pediatric cancer patients with - [Gene-by-Environment Interactions Involving Maternal Exposures with Orofacial Cleft Risk in Filipinos](https://kidsfirstdrc.org/publication/gene-by-environment-interactions-involving-maternal-exposures-with-orofacial-cleft-risk-in-filipinos/) - Background/objectives: Maternal exposures are known to influence the risk of isolated cleft lip with or without cleft palate (CL/P)-a common and highly heritable birth defect with a multifactorial etiology. Methods: To identify new risk loci, we conducted a genome-wide gene-environment interaction (GEI) analysis of CL/P with maternal smoking and vitamin use in Filipinos (Ncases = 540, Ncontrols = 260). Since - [Novel Protein-Altering Variants in Cleft Genes Transmitted in Families With NSCL±P](https://kidsfirstdrc.org/publication/novel-protein-altering-variants-in-cleft-genes-transmitted-in-families-with-nscl±p/) - Background: Pathogenic protein-altering variants play a role in the etiology of nonsyndromic cleft lip with or without palate (nsCL±P), one of the most common craniofacial anomalies. However, the genetic basis of many cases remains unclear, complicating risk prediction for affected families. Purpose: This study utilized whole-genome sequencing (WGS) of 150 case-families with nsCL±P from sub-Saharan Africa to - [USP7 alterations are associated with a poor survival in pediatric T-cell Acute Lymphoblastic Leukemia](https://kidsfirstdrc.org/publication/usp7-alterations-are-associated-with-a-poor-survival-in-pediatric-t-cell-acute-lymphoblastic-leukemia/) - Less than 25% of relapsed pediatric T-ALL patients survive, highlighting the need to identify them beforehand. Here, we show that USP7 SNVs, combined with MRD and CNS status, could identify very-high risk patients, offering novel insights for risk stratification. - [Functional Annotation of De Novo Variants Found Near GWAS Loci Associated With Cleft Lip With or Without Cleft Palate](https://kidsfirstdrc.org/publication/functional-annotation-of-de-novo-variants-found-near-gwas-loci-associated-with-cleft-lip-with-or-without-cleft-palate/) - Background: Orofacial clefts (OFCs) are the most common craniofacial birth defects, affecting 1 in 700 births, and have a strong genetic basis with a high recurrence risk within families. Aims: While many of the previous studies have associated common, noncoding genetic loci with OFCs, previous studies on de novo variants (DNVs) in OFC cases have focused on - [Expanding and refining the mammalian phenotype ontology to enhance disease model discovery](https://kidsfirstdrc.org/publication/expanding-and-refining-the-mammalian-phenotype-ontology-to-enhance-disease-model-discovery/) - The mouse is a premier model system for investigating gene function and modeling human disease. For almost 40 years, Mouse Genome Informatics has worked to capture and integrate the data generated from mouse studies. A critical component of this integration is the development and use of the Mammalian Phenotype (MP) ontology to capture the morphological - [Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detection](https://kidsfirstdrc.org/publication/advancing-long-read-nanopore-genome-assembly-and-accurate-variant-calling-for-rare-disease-detection/) - More than 50% of families with suspected rare monogenic diseases remain unsolved after whole-genome analysis by short-read sequencing (SRS). Long-read sequencing (LRS) could help bridge this diagnostic gap by capturing variants inaccessible to SRS, facilitating long-range mapping and phasing and providing haplotype-resolved methylation profiling. To evaluate LRS's additional diagnostic yield, we sequenced a rare-disease cohort - [NRCAM variant defined by microexon skipping is a targetable cell surface proteoform in high-grade gliomas](https://kidsfirstdrc.org/publication/nrcam-variant-defined-by-microexon-skipping-is-a-targetable-cell-surface-proteoform-in-high-grade-gliomas/) - To overcome the paucity of known tumor-specific surface antigens in pediatric high-grade glioma (pHGG), we contrasted splicing patterns in pHGGs and normal brain samples. Among alternative splicing events affecting extracellular protein domains, the most pervasive alteration was the skipping of ≤30-nt-long exons. Several of these skipped microexons mapped to L1-immunoglobulin cell adhesion molecule (IgCAM) family - [Fusion Oncoproteins and Cooperating Mutations Define Disease Phenotypes in NUP98-Rearranged Leukemia](https://kidsfirstdrc.org/publication/fusion-oncoproteins-and-cooperating-mutations-define-disease-phenotypes-in-nup98-rearranged-leukemia/) - Leukemias with NUP98 rearrangements exhibit heterogeneous phenotypes such as acute myeloid leukemia (AML), T-acute lymphoblastic leukemia (T-ALL), or myelodysplastic syndrome/neoplasms (MDS) associated with fusion partners, whereas the mechanism responsible for this heterogeneity is poorly understood. Through genome-wide mutational and transcriptional analyses of 177 NUP98-rearranged leukemias, we show that cooperating alterations are associated with differentiation status - [EPHA4 signaling dysregulation links abnormal locomotion and the development of idiopathic scoliosis](https://kidsfirstdrc.org/publication/epha4-signaling-dysregulation-links-abnormal-locomotion-and-the-development-of-idiopathic-scoliosis/) - Idiopathic scoliosis (IS) is the most common form of spinal deformity with unclear pathogenesis. In this study, we first reanalyzed the loci associated with IS, drawing upon previous studies. Subsequently, we mapped these loci to candidate genes using either location-based or function-based strategies. To further substantiate our findings, we verified the enrichment of variants within - [Rare variants in PRKCI cause Van der Woude syndrome and other features of peridermopathy](https://kidsfirstdrc.org/publication/rare-variants-in-prkci-cause-van-der-woude-syndrome-and-other-features-of-peridermopathy/) - Van der Woude syndrome (VWS) is an autosomal dominant disorder characterized by lower lip pits and orofacial clefts (OFCs). With a prevalence of ∼1 in 35,000 live births, it is the most common form of syndromic clefting. Most VWS is attributed to variants in IRF6 (∼70%) or GRHL3 (∼5%), leaving up to 25% of individuals - [Role of stem-like cells in chemotherapy resistance and relapse in pediatric T-cell acute lymphoblastic leukemia](https://kidsfirstdrc.org/publication/role-of-stem-like-cells-in-chemotherapy-resistance-and-relapse-in-pediatric-t-cell-acute-lymphoblastic-leukemia/) - T-ALL relapses are characterized by chemotherapy resistance, cellular diversity and dismal outcome. To gain a deeper understanding of the mechanisms underlying relapses, we conduct single-cell RNA sequencing on 13 matched pediatric T-ALL patient-derived samples at diagnosis and relapse, along with samples derived from 5 non-relapsing patients collected at diagnosis. This comprehensive longitudinal single-cell study in - [Distinct Mitochondrial DNA Deletion Profiles in Pediatric B- and T-ALL During Diagnosis, Remission, and Relapse](https://kidsfirstdrc.org/publication/distinct-mitochondrial-dna-deletion-profiles-in-pediatric-b-and-t-all-during-diagnosis-remission-and-relapse/) - Mitochondria are critical for cellular energy, and while large deletions in their genome (mtDNA) are linked to primary mitochondrial diseases, their significance in cancer is less understood. Given cancer's metabolic nature, investigating mtDNA deletions in tumors at various stages could provide insights into disease origins and treatment responses. In this study, we analyzed 148 bone - [Genomic rare variant mechanisms for congenital cardiac laterality defect: A digenic model approach](https://kidsfirstdrc.org/publication/genomic-rare-variant-mechanisms-for-congenital-cardiac-laterality-defect-a-digenic-model-approach/) - Laterality defects are defined by perturbations in the usual left-right asymmetry of organs. The genetic etiology that underlies congenital heart disease (CHD) is often unknown (less than 40%), so we used a digenic model approach for the identification of contributing variants in known laterality-defect-associated genes (n = 115) in the exome/genome sequencing (ES/GS) data from - [The Contribution of De Novo Coding Mutations to Meningomyelocele](https://kidsfirstdrc.org/publication/the-contribution-of-de-novo-coding-mutations-to-meningomyelocele/) - Meningomyelocele (also known as spina bifida) is considered to be a genetically complex disease resulting from a failure of the neural tube to close. Individuals with meningomyelocele display neuromotor disability and frequent hydrocephalus, requiring ventricular shunting. A few genes have been proposed to contribute to disease susceptibility, but beyond that it remains unexplained1. We postulated - [Clinical and molecular features of pediatric cancer patients with Lynch syndrome](https://kidsfirstdrc.org/publication/clinical-and-molecular-features-of-pediatric-cancer-patients-with-lynch-syndrome-2/) - Background: The association of childhood cancer with Lynch syndrome is not established compared with the significant pediatric cancer risk in recessive constitutional mismatch repair deficiency syndrome (CMMRD). Procedure: We describe the clinical features, germline analysis, and tumor genomic profiling of patients with Lynch syndrome among patients enrolled in pediatric cancer genomic studies. Results: There were - [Protocol to analyze deep-learning-predicted functional scores for noncoding de novo variants and their correlation with complex brain traits](https://kidsfirstdrc.org/publication/protocol-to-analyze-deep-learning-predicted-functional-scores-for-noncoding-de-novo-variants-and-their-correlation-with-complex-brain-traits/) - Functional impact of noncoding variants can be predicted using computational approaches. Although predictive scores can be insightful, implementing the scores for a custom variant set and associating scores with complex traits require multiple phases of analysis. Here, we present a protocol for prioritizing variants by generating deep-learning-predicted functional scores and relating them with brain traits. - [Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders](https://kidsfirstdrc.org/publication/expanding-the-genetics-and-phenotypes-of-ocular-congenital-cranial-dysinnervation-disorders/) - Purpose: This study aimed to identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs). Methods: We coupled phenotyping with exome or genome sequencing of 467 probands (550 affected and 1108 total individuals) with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare - [Multiparametric MRI along with machine learning predicts prognosis and treatment response in pediatric low-grade glioma](https://kidsfirstdrc.org/publication/multiparametric-mri-along-with-machine-learning-predicts-prognosis-and-treatment-response-in-pediatric-low-grade-glioma/) - Pediatric low-grade gliomas (pLGGs) exhibit heterogeneous prognoses and variable responses to treatment, leading to tumor progression and adverse outcomes in cases where complete resection is unachievable. Early prediction of treatment responsiveness and suitability for immunotherapy has the potential to improve clinical management and outcomes. Here, we present a radiogenomic analysis of pLGGs, integrating MRI and - [M&M: an RNA-seq based pan-cancer classifier for paediatric tumours](https://kidsfirstdrc.org/publication/mm-an-rna-seq-based-pan-cancer-classifier-for-paediatric-tumours/) - Background: With many rare tumour types, acquiring the correct diagnosis is a challenging but crucial process in paediatric oncology. Historically, this is done based on histology and morphology of the disease. However, advances in genome wide profiling techniques such as RNA sequencing now allow the development of molecular classification tools. Methods: Here, we present M&M, a pan-paediatric - [Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution](https://kidsfirstdrc.org/publication/ongoing-chromothripsis-underpins-osteosarcoma-genome-complexity-and-clonal-evolution/) - Osteosarcoma is the most common primary cancer of the bone, with a peak incidence in children and young adults. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of osteosarcomas. Chromothripsis generates highly unstable derivative chromosomes, the ongoing evolution of which drives the acquisition of oncogenic mutations, - [Lineage dependence of the neuroblastoma surfaceome defines tumor cell state-dependent and -independent immunotherapeutic targets](https://kidsfirstdrc.org/publication/lineage-dependence-of-the-neuroblastoma-surfaceome-defines-tumor-cell-state-dependent-and-independent-immunotherapeutic-targets/) - Background: Neuroblastoma is a heterogeneous disease with adrenergic (ADRN)-like cells and therapy-resistant mesenchymal (MES)-like cells driven by distinct transcription factor networks. Here, we investigate the expression of immunotherapeutic targets in each neuroblastoma subtype and propose pan-neuroblastoma and cell state-specific targetable cell surface proteins. Methods: We characterized cell lines, patient-derived xenografts, and patient samples as ADRN-dominant or MES-dominant - [Genetic ancestry superpopulations show distinct prevalence and outcomes across pediatric central nervous system tumors from the PBTA and PNOC](https://kidsfirstdrc.org/publication/genetic-ancestry-superpopulations-show-distinct-prevalence-and-outcomes-across-pediatric-central-nervous-system-tumors-from-the-pbta-and-pnoc/) - Background: Central nervous system (CNS) tumors lead to cancer-related mortality in children. Genetic ancestry-associated cancer prevalence and outcomes have been studied but are limited. Methods: We performed genetic ancestry prediction in 1,452 pediatric patients with paired normal and tumor whole genome sequencing from the Open Pediatric Cancer (OpenPedCan) project to evaluate the influence of reported race and - [Single-cell panleukemia signatures of HSPC-like blasts predict drug response and clinical outcome](https://kidsfirstdrc.org/publication/single-cell-panleukemia-signatures-of-hspc-like-blasts-predict-drug-response-and-clinical-outcome/) - The critical role of leukemia-initiating cells as a therapy-resistant population in myeloid leukemia is well established. However, the molecular signatures of such cells in acute lymphoblastic leukemia remain underexplored. Moreover, their role in therapy response and patient prognosis is yet to be systematically investigated across various types of acute leukemia. We used single-cell multiomics to - [Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes, including short stature, scoliosis, and skeletal dysplasia](https://kidsfirstdrc.org/publication/biallelic-slc13a1-loss-of-function-variants-result-in-impaired-sulfate-transport-and-skeletal-phenotypes-including-short-stature-scoliosis-and-skeletal-dysplasia/) - Purpose: Sulfate is vital for many physiological processes, including the structural and functional maintenance of macromolecules and formation of sulfur-containing compounds essential for cartilage and bone development. SLC13A1 is a sodium-sulfate cotransporter primarily expressed in the kidney, where it mediates sulfate reabsorption and maintenance of circulating sulfate levels. In this study, we characterized the clinical, biochemical, - [Genome-wide CRISPR screen identifies IRF1 and TFAP4 as transcriptional regulators of Galectin-9 in T cell acute lymphoblastic leukemia](https://kidsfirstdrc.org/publication/genome-wide-crispr-screen-identifies-irf1-and-tfap4-as-transcriptional-regulators-of-galectin-9-in-t-cell-acute-lymphoblastic-leukemia/) - Galectin-9 is overexpressed in a variety of cancers and associated with worse clinical outcome in some cancers. However, the regulators driving Galectin-9 expression are unknown. Here, we defined the transcriptional regulators and epigenetic circuitry of Galectin-9 in pediatric T cell acute lymphoblastic leukemia (T-ALL), as an example of a disease with strong Galectin-9 expression, in - [GATA2 links stemness to chemotherapy resistance in acute myeloid leukemia](https://kidsfirstdrc.org/publication/gata2-links-stemness-to-chemotherapy-resistance-in-acute-myeloid-leukemia/) - Stemness-associated cell states are linked to chemotherapy resistance in acute myeloid leukemia (AML). We uncovered a direct mechanistic link between expression of the stem cell transcription factor GATA2 and drug resistance. The GATA-binding protein 2 (GATA2) plays a central role in blood stem cell generation and maintenance. We find substantial intrapatient and interpatient variability in - [STAT1-mediated interferon signatures associate with preclinical JAK-inhibitor sensitivity in T-cell acute lymphoblastic leukemia](https://kidsfirstdrc.org/publication/stat1-mediated-interferon-signatures-associate-with-preclinical-jak-inhibitor-sensitivity-in-t-cell-acute-lymphoblastic-leukemia/) - We used single-cell genomics to characterize a patient with T-cell acute lymphoblastic leukemia treated in the Children's Oncology Group AALL0434 trial with poor clinical outcome despite favorable genomic features, identifying a STAT1-mediated interferon-related transcriptional signature and inflammatory microenvironment associated with sensitivity to small-molecule JAK inhibition. - [Gene Identification for Ocular Congenital Cranial Motor Neuron Disorders Using Human Sequencing, Zebrafish Screening, and Protein Binding Microarrays](https://kidsfirstdrc.org/publication/gene-identification-for-ocular-congenital-cranial-motor-neuron-disorders-using-human-sequencing-zebrafish-screening-and-protein-binding-microarrays/) - Purpose: To functionally evaluate novel human sequence-derived candidate genes and variants for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs). Methods: Through exome and genome sequencing of a genetically unsolved human oCCDD cohort, we previously reported the identification of variants in many candidate genes. Here, we describe a parallel study that prioritized a subset of these genes (43 - [Efficient identification of de novo mutations in family trios: a consensus-based informatic approach](https://kidsfirstdrc.org/publication/efficient-identification-of-de-novo-mutations-in-family-trios-a-consensus-based-informatic-approach/) - Accurate identification of de novo variants (DNVs) remains challenging despite advances in sequencing technologies, often requiring ad hoc filters and manual inspection. Here, we explored a purely informatic, consensus-based approach for identifying DNVs in proband-parent trios using short-read genome sequencing data. We evaluated variant calls generated by three sequence analysis pipelines-GATK HaplotypeCaller, DeepTrio, and Velsera - [Evaluating the Potential of PSMA Targeting in CNS Tumors: Insights from Large-Scale Transcriptome Profiling](https://kidsfirstdrc.org/publication/evaluating-the-potential-of-psma-targeting-in-cns-tumors-insights-from-large-scale-transcriptome-profiling/) - Background/objectives: Prostate-specific membrane antigen (PSMA) is a well-established target in prostate cancer therapy that has shown potential as a theranostic target across non-central nervous system (CNS) and CNS tumor types. We aimed to investigate the pan-tissue expression pattern of the PSMA-encoding gene FOLH1 to assess whether transcriptome profiling can inform tumor diagnostic and theranostic probes. Methods: We - [Common cis-regulatory variation modifies the penetrance of pathogenic SHROOM3 variants in craniofacial microsomia](https://kidsfirstdrc.org/publication/common-cis-regulatory-variation-modifies-the-penetrance-of-pathogenic-shroom3-variants-in-craniofacial-microsomia-2/) - Pathogenic coding variants have been identified in thousands of genes, yet the mechanisms underlying the incomplete penetrance in individuals carrying these variants are poorly understood. In this study, in a cohort of 2009 craniofacial microsomia (CFM) patients of Chinese ancestry and 2625 Han Chinese controls, we identified multiple predicted pathogenic coding variants in SHROOM3 in both CFM - [A multiomic atlas identifies a treatment-resistant, bone marrow progenitor-like cell population in T cell acute lymphoblastic leukemia](https://kidsfirstdrc.org/publication/a-multiomic-atlas-identifies-a-treatment-resistant-bone-marrow-progenitor-like-cell-population-in-t-cell-acute-lymphoblastic-leukemia/) - Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to curing T cell acute lymphoblastic leukemia (T-ALL). While tumor heterogeneity has been implicated in treatment failure, the cellular and genetic factors contributing to resistance and relapse remain unknown. Here we linked tumor subpopulations with clinical outcome, created an atlas of healthy pediatric - [Copy number variations contribute to malignant tumor development in children with serious birth defects](https://kidsfirstdrc.org/publication/copy-number-variations-contribute-to-malignant-tumor-development-in-children-with-serious-birth-defects/) - There are two key signatures of pediatric cancers: (a) higher prevalence of germline alterations and (b) heterogeneity in alteration types. Recent population-based assessments have demonstrated that children with birth defects (BDs) are more likely to develop cancer even without chromosomal anomalies; therefore, explorations of genetic alterations in children with BDs and cancers could provide new - [Deep learning algorithms reveal genomic markers for anxiety disorder in a large cohort of children with down syndrome](https://kidsfirstdrc.org/publication/deep-learning-algorithms-reveal-genomic-markers-for-anxiety-disorder-in-a-large-cohort-of-children-with-down-syndrome/) - Despite a significant burden of neurobehavioral and psychiatric comorbidities in children with Down syndrome (DS), and the general increased risk for anxiety in individuals with intellectual disabilities (ID), children with DS have significantly lower odds of anxiety. Understanding the specific mechanisms of anxiety in DS could inform the development of new treatments. This study performed - [Fundamentals of FAIR biomedical data analyses in the cloud using custom pipelines](https://kidsfirstdrc.org/publication/fundamentals-of-fair-biomedical-data-analyses-in-the-cloud-using-custom-pipelines/) - As the biomedical data ecosystem increasingly embraces the findable, accessible, interoperable, and reusable (FAIR) data principles to publish multimodal datasets to the cloud, opportunities for cloud-based research continue to expand. Besides the potential for accelerated and diverse biomedical discovery that comes from a harmonized data ecosystem, the cloud also presents a shift away from the - [Genome-wide association study of somatic GATA1s mutations in newborns with Down Syndrome](https://kidsfirstdrc.org/publication/genome-wide-association-study-of-somatic-gata1s-mutations-in-newborns-with-down-syndrome/) - Myeloid Leukemia of Down Syndrome (ML-DS) is preceded by a transient neonatal preleukemia driven by somatic mutations in the chromosome X gene GATA1, resulting in a shorter protein isoform (GATA1s). GATA1s mutations occur at high frequency in DS but beyond trisomy 21, risk factors for this preleukemia are unknown. We investigated whether germline genetic variation - [Genome-Wide Association Studies of Down Syndrome Associated Congenital Heart Defects Suggests a Genetically Heterogeneous Risk for CHD in DS](https://kidsfirstdrc.org/publication/genome-wide-association-studies-of-down-syndrome-associated-congenital-heart-defects-suggests-a-genetically-heterogeneous-risk-for-chd-in-ds/) - Congenital heart defects (CHDs) are the most common structural birth defect and are present in 40%-50% of children born with Down syndrome (DS). To characterize the genetic architecture of DS-associated CHD, we sequenced genomes of a multiethnic group of children with DS and a CHD (n = 886: atrioventricular septal defects (AVSD), n = 438; - [Homo Sapiens Chromosomal Location Ontology: A Framework for Genomic Data in Biomedical Knowledge Graphs](https://kidsfirstdrc.org/publication/homo-sapiens-chromosomal-location-ontology-a-framework-for-genomic-data-in-biomedical-knowledge-graphs/) - The Homo sapiens Chromosomal Location Ontology (HSCLO) is designed to facilitate the integration of human genomic features into biomedical knowledge graphs from releases GRCh37 and GRCh38 at multiple resolutions. HSCLO comprises two distinct versions, HSCLO37 and HSCLO38, each tailored to its respective human genome release. This ontology supports the efficient integration and analysis of human - [Impact of Genetic Ancestry on Genomics and Survival Outcomes in T-cell Acute Lymphoblastic Leukemia](https://kidsfirstdrc.org/publication/impact-of-genetic-ancestry-on-genomics-and-survival-outcomes-in-t-cell-acute-lymphoblastic-leukemia/) - The influence of genetic ancestry on genomics in T-cell Acute Lymphoblastic Leukemia (T-ALL) has not been fully explored. We examined the impact of genetic ancestry on multi-omic alterations, survival outcomes, and risk stratification. Among 1309 children and young adults with T-ALL treated on the Children's Oncology Group trial AALL0434, the prognostic value of five commonly - [Risk of Alzheimer's disease in Down syndrome: Insights gained by multi-omics](https://kidsfirstdrc.org/publication/risk-of-alzheimers-disease-in-down-syndrome-insights-gained-by-multi-omics/) - Individuals with Down syndrome (DS) are highly susceptible to Alzheimer's disease (AD). The integration of genomics, transcriptomics, epigenomics, proteomics, and metabolomics enables unprecedented understanding of DS-AD, offering a detailed picture of this complex issue. The vast -omics data also present challenges that reflect the complexity of genetic information flow. These studies nonetheless reveal critical mechanisms - [Systematic phenotype and genotype characterization of Moebius syndrome](https://kidsfirstdrc.org/publication/systematic-phenotype-and-genotype-characterization-of-moebius-syndrome/) - Purpose: To explore the phenotypic spectrum and genetic etiologies of Moebius Syndrome (MBS), a rare neurological disorder defined by congenital, nonprogressive facial weakness and limitations in ocular abduction. Methods: We applied strict diagnostic criteria and conducted clinical phenotyping of 149 individuals with MBS. Subsequently, we performed exome and/or genome sequencing on 67 of these individuals and 117 - [Pediatric high-grade glioma resources from the Children's Brain Tumor Tissue Consortium](https://kidsfirstdrc.org/publication/pediatric-high-grade-glioma-resources-from-the-childrens-brain-tumor-tissue-consortium/) - Pediatric high-grade gliomas (pHGGs) are a leading cause of pediatric cancer death but are genomically and spatially distinct. In this report we describe the generation and characterization of pHGG reagents with linked genomic and longitudinal clinical data freely available to the community to accelerate pHGG research. - [Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations](https://kidsfirstdrc.org/publication/loss-of-function-variants-in-ppp1r12a-from-isolated-sex-reversal-to-holoprosencephaly-spectrum-and-urogenital-malformations/) - In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has - [Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development](https://kidsfirstdrc.org/publication/novel-variants-in-tuba1a-cause-congenital-fibrosis-of-the-extraocular-muscles-with-or-without-malformations-of-cortical-brain-development/) - Variants in multiple tubulin genes have been implicated in neurodevelopmental disorders, including malformations of cortical development (MCD) and congenital fibrosis of the extraocular muscles (CFEOM). Distinct missense variants in the beta-tubulin encoding genes TUBB3 and TUBB2B cause MCD, CFEOM, or both, suggesting substitution-specific mechanisms. Variants in the alpha tubulin-encoding gene TUBA1A have been associated with - [Genome-Wide Association Study of Non-syndromic Orofacial Clefts in a Multiethnic Sample of Families and Controls Identifies Novel Regions](https://kidsfirstdrc.org/publication/genome-wide-association-study-of-non-syndromic-orofacial-clefts-in-a-multiethnic-sample-of-families-and-controls-identifies-novel-regions/) - Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic and vary in prevalence by ethnicity. Africans have the lowest prevalence of OFCs (~ 1/2,500), Asians have the highest prevalence (~1/500), Europeans and Latin Americans lie somewhere in the middle - [Prognostic implications of immune-related eight-gene signature in pediatric brain tumors](https://kidsfirstdrc.org/publication/prognostic-implications-of-immune-related-eight-gene-signature-in-pediatric-brain-tumors/) - Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors (PBT) that may lead to novel therapeutic strategies. Participants of the cohort Pediatric Brain Tumor Atlas: CBTTC (CBTTC cohort), were randomly divided into training and validation cohorts. In the training cohort, Kaplan-Meier analysis and univariate Cox regression model were applied - [CXCL14 Promotes a Robust Brain Tumor-Associated Immune Response in Glioma](https://kidsfirstdrc.org/publication/cxcl14-promotes-a-robust-brain-tumor-associated-immune-response-in-glioma/) - Purpose: The immunosuppressive tumor microenvironment present in the majority of diffuse glioma limits therapeutic response to immunotherapy. As the determinants of the glioma-associated immune response are relatively poorly understood, the study of glioma with more robust tumor-associated immune responses may be particularly useful to identify novel immunomodulatory factors that can promote T-cell effector function in glioma. - [Mitochondrial DNA haplogroup, genetic ancestry, and susceptibility to Ewing sarcoma](https://kidsfirstdrc.org/publication/mitochondrial-dna-haplogroup-genetic-ancestry-and-susceptibility-to-ewing-sarcoma/) - Based on current studies, the incidence of Ewing sarcoma (ES) varies significantly by race and ethnicity, with the disease being most common in patients of European ancestry. However, race/ethnicity has generally been self-reported rather than formally evaluated at a population level using DNA evidence. Additionally, mitochondrial dysfunction is a hallmark of ES, yet there have - [Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate](https://kidsfirstdrc.org/publication/damaging-mutations-in-afdn-contribute-to-risk-of-nonsyndromic-cleft-lip-with-or-without-cleft-palate/) - Novel or rare damaging mutations have been implicated in the developmental pathogenesis of nonsyndromic cleft lip with or without cleft palate (nsCL ± P). Thus, we investigated the human genome for high-impact mutations that could explain the risk of nsCL ± P in our cohorts. We conducted next-generation sequencing (NGS) analysis of 130 nsCL ± - [Unsupervised machine learning using K-means identifies radiomic subgroups of pediatric low-grade gliomas that correlate with key molecular markers](https://kidsfirstdrc.org/publication/unsupervised-machine-learning-using-k-means-identifies-radiomic-subgroups-of-pediatric-low-grade-gliomas-that-correlate-with-key-molecular-markers/) - Introduction: Despite advancements in molecular and histopathologic characterization of pediatric low-grade gliomas (pLGGs), there remains significant phenotypic heterogeneity among tumors with similar categorizations. We hypothesized that an unsupervised machine learning approach based on radiomic features may reveal distinct pLGG imaging subtypes. Methods: Multi-parametric MR images (T1 pre- and post-contrast, T2, and T2 FLAIR) from 157 patients with - [Methyltransferase Inhibition Enables Tgf β Driven Induction of CDKN2A and B in Cancer Cells](https://kidsfirstdrc.org/publication/methyltransferase-inhibition-enables-tgf-β-driven-induction-of-cdkn2a-and-b-in-cancer-cells/) - CDKN2A/B deletion or silencing is common across human cancer, reinforcing the general importance of bypassing its tumor suppression in cancer formation or progression. In rhabdomyosarcoma (RMS) and neuroblastoma, two common childhood cancers, the three CDKN2A/B transcripts are independently expressed to varying degrees, but one, ARF, is uniformly silenced. Although TGFβ induces certain CDKN2A/B transcripts in HeLa cells, it was unable to do - [Genetic predisposition to neuroblastoma results from a regulatory polymorphism that promotes the adrenergic cell state](https://kidsfirstdrc.org/publication/genetic-predisposition-to-neuroblastoma-results-from-a-regulatory-polymorphism-that-promotes-the-adrenergic-cell-state/) - Childhood neuroblastomas exhibit plasticity between an undifferentiated neural crest-like mesenchymal cell state and a more differentiated sympathetic adrenergic cell state. These cell states are governed by autoregulatory transcriptional loops called core regulatory circuitries (CRCs), which drive the early development of sympathetic neuronal progenitors from migratory neural crest cells during embryogenesis. The adrenergic cell identity of - [Toxicology knowledge graph for structural birth defects](https://kidsfirstdrc.org/publication/toxicology-knowledge-graph-for-structural-birth-defects/) - Background: Birth defects are functional and structural abnormalities that impact about 1 in 33 births in the United States. They have been attributed to genetic and other factors such as drugs, cosmetics, food, and environmental pollutants during pregnancy, but for most birth defects there are no known causes. Methods: To further characterize associations between small molecule compounds - [Genomic information of children with malignant brain tumors for the prediction of length of hospitalization](https://kidsfirstdrc.org/publication/genomic-information-of-children-with-malignant-brain-tumors-for-the-prediction-of-length-of-hospitalization/) - [Parents and Provider Perspectives on the Return of Genomic Findings for Cleft Families in Africa](https://kidsfirstdrc.org/publication/parents-and-provider-perspectives-on-the-return-of-genomic-findings-for-cleft-families-in-africa/) - Background: Inadequate knowledge among health care providers (HCPs) and parents of affected children limits the understanding and utility of secondary genetic findings (SFs) in under-represented populations in genomics research. SFs arise from deep DNA sequencing done for research or diagnostic purposes and may burden patients and their families despite their potential health importance. This study aims - [Biologic and Clinical Analysis of Childhood Gamma Delta T-ALL Identifies LMO2/STAG2 Rearrangements as Extremely High Risk](https://kidsfirstdrc.org/publication/biologic-and-clinical-analysis-of-childhood-gamma-delta-t-all-identifies-lmo2-stag2-rearrangements-as-extremely-high-risk/) - Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under - [The genomic basis of childhood T-lineage acute lymphoblastic leukaemia](https://kidsfirstdrc.org/publication/the-genomic-basis-of-childhood-t-lineage-acute-lymphoblastic-leukaemia/) - T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour1 that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation2,3. Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with - [Functional analysis of ESRP1/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis](https://kidsfirstdrc.org/publication/functional-analysis-of-esrp1-2-gene-variants-and-ctnnd1-isoforms-in-orofacial-cleft-pathogenesis/) - Orofacial cleft (OFC) is a common human congenital anomaly. Epithelial-specific RNA splicing regulators ESRP1 and ESRP2 regulate craniofacial morphogenesis and their disruption result in OFC in zebrafish, mouse and humans. Using esrp1/2 mutant zebrafish and murine Py2T cell line models, we functionally tested the pathogenicity of human ESRP1/2 gene variants. We found that many variants - [Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants](https://kidsfirstdrc.org/publication/common-variants-increase-risk-for-congenital-diaphragmatic-hernia-within-the-context-of-de-novo-variants/) - Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 - [A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders](https://kidsfirstdrc.org/publication/a-cell-type-aware-framework-for-nominating-non-coding-variants-in-mendelian-regulatory-disorders/) - Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set - [Deciphering protective genomic factors of tumor development in pediatric Down syndrome via deep learning approach to whole genome and RNA sequencing](https://kidsfirstdrc.org/publication/deciphering-protective-genomic-factors-of-tumor-development-in-pediatric-down-syndrome-via-deep-learning-approach-to-whole-genome-and-rna-sequencing/) - [TRIO RVEMVS: A Bayesian framework for rare variant association analysis with expectation-maximization variable selection using family trio data](https://kidsfirstdrc.org/publication/trio-rvemvs-a-bayesian-framework-for-rare-variant-association-analysis-with-expectation-maximization-variable-selection-using-family-trio-data/) - It is commonly reported that rare variants may be more functionally related to complex diseases than common variants. However, individual rare variant association tests remain challenging due to low minor allele frequency in the available samples. This paper proposes an expectation maximization variable selection (EMVS) method to simultaneously detect common and rare variants at the - [Petagraph: A large-scale unifying knowledge graph framework for integrating biomolecular and biomedical data](https://kidsfirstdrc.org/publication/petagraph-a-large-scale-unifying-knowledge-graph-framework-for-integrating-biomolecular-and-biomedical-data/) - Over the past decade, there has been substantial growth in both the quantity and complexity of available biomedical data. In order to more efficiently harness this extensive data and alleviate challenges associated with integration of multi-omics data, we developed Petagraph, a biomedical knowledge graph that encompasses over 32 million nodes and 118 million relationships. Petagraph - [Genomic frontiers in congenital heart disease](https://kidsfirstdrc.org/publication/genomic-frontiers-in-congenital-heart-disease/) - The application of next-generation sequencing to study congenital heart disease (CHD) is increasingly providing new insights into the causes and mechanisms of this prevalent birth anomaly. Whole-exome sequencing analysis identifies damaging gene variants altering single or contiguous nucleotides that are assigned pathogenicity based on statistical analyses of families and cohorts with CHD, high expression in - [A structural variation reference for medical and population genetics](https://kidsfirstdrc.org/publication/a-structural-variation-reference-for-medical-and-population-genetics/) - Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no - [M-DATA: A statistical approach to jointly analyzing de novo mutations for multiple traits](https://kidsfirstdrc.org/publication/m-data-a-statistical-approach-to-jointly-analyzing-de-novo-mutations-for-multiple-traits/) - Recent studies have demonstrated that multiple early-onset diseases have shared risk genes, based on findings from de novo mutations (DNMs). Therefore, we may leverage information from one trait to improve statistical power to identify genes for another trait. However, there are few methods that can jointly analyze DNMs from multiple traits. In this study, we - [Genome-Wide De Novo Variants in Congenital Heart Disease Are Not Associated With Maternal Diabetes or Obesity](https://kidsfirstdrc.org/publication/genome-wide-de-novo-variants-in-congenital-heart-disease-are-not-associated-with-maternal-diabetes-or-obesity/) - Background: Congenital heart disease (CHD) is the most common anomaly at birth, with a prevalence of ≈1%. While infants born to mothers with diabetes or obesity have a 2- to 3-fold increased incidence of CHD, the cause of the increase is unknown. Damaging de novo variants (DNV) in coding regions are more common among patients with - [A Bright Horizon: Immunotherapy for Pediatric T-Cell Malignancies](https://kidsfirstdrc.org/publication/a-bright-horizon-immunotherapy-for-pediatric-t-cell-malignancies/) - Immunotherapy has transformed the treatment of hematologic malignancies in the past two decades. The treatment of acute lymphoblastic leukemia (ALL), in particular, has been highly impacted by multiple novel immunotherapies. For pediatric patients with T-cell malignancies, translating immunotherapies has proved more challenging due to the complexities of fratricide, risk of product contamination with malignant cells, - [BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma](https://kidsfirstdrc.org/publication/bard1-germline-variants-induce-haploinsufficiency-and-dna-repair-defects-in-neuroblastoma/) - Background: High-risk neuroblastoma is a complex genetic disease that is lethal in more than 50% of patients despite intense multimodal therapy. Through genome-wide association studies (GWAS) and next-generation sequencing, we have identified common single nucleotide polymorphisms and rare, pathogenic or likely pathogenic germline loss-of-function variants in BARD1 enriched in neuroblastoma patients. The functional implications of these - [MRD at the end of induction and EFS in T-cell lymphoblastic lymphoma: Children's Oncology Group trial AALL1231](https://kidsfirstdrc.org/publication/mrd-at-the-end-of-induction-and-efs-in-t-cell-lymphoblastic-lymphoma-childrens-oncology-group-trial-aall1231/) - Defining prognostic variables in T-lymphoblastic lymphoma (T-LL) remains a challenge. AALL1231 was a Children's Oncology Group phase 3 clinical trial for newly diagnosed patients with T acute lymphoblastic leukemia or T-LL, randomizing children and young adults to a modified augmented Berlin-Frankfurt-Münster backbone to receive standard therapy (arm A) or with addition of bortezomib (arm B). - [Beyond the Human Genome Project: The Age of Complete Human Genome Sequences and Pangenome References](https://kidsfirstdrc.org/publication/beyond-the-human-genome-project-the-age-of-complete-human-genome-sequences-and-pangenome-references/) - The Human Genome Project was an enormous accomplishment, providing a foundation for countless explorations into the genetics and genomics of the human species. Yet for many years, the human genome reference sequence remained incomplete and lacked representation of human genetic diversity. Recently, two major advances have emerged to address these shortcomings: complete gap-free human genome - [Increased endothelial sclerostin caused by elevated DSCAM mediates multiple trisomy 21 phenotypes](https://kidsfirstdrc.org/publication/increased-endothelial-sclerostin-caused-by-elevated-dscam-mediates-multiple-trisomy-21-phenotypes/) - Trisomy 21 (T21), a recurrent aneuploidy occurring in 1:800 births, predisposes to congenital heart disease (CHD) and multiple extracardiac phenotypes. Despite a definitive genetic etiology, the mechanisms by which T21 perturbs development and homeostasis remain poorly understood. We compared the transcriptome of CHD tissues from 49 patients with T21 and 226 with euploid CHD (eCHD). - [Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings](https://kidsfirstdrc.org/publication/next-generation-phenotyping-integrated-in-a-national-framework-for-patients-with-ultrarare-disorders-improves-genetic-diagnostics-and-yields-new-molecular-findings/) - Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients - [A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability](https://kidsfirstdrc.org/publication/a-phenome-wide-association-study-of-methylated-gc-rich-repeats-identifies-a-gcc-repeat-expansion-in-aff3-associated-with-intellectual-disability/) - GC-rich tandem repeat expansions (TREs) are often associated with DNA methylation, gene silencing and folate-sensitive fragile sites, and underlie several congenital and late-onset disorders. Through a combination of DNA-methylation profiling and tandem repeat genotyping, we identified 24 methylated TREs and investigated their effects on human traits using phenome-wide association studies in 168,641 individuals from the - [High-coverage nanopore sequencing of samples from the 1000 Genomes Project to build a comprehensive catalog of human genetic variation](https://kidsfirstdrc.org/publication/high-coverage-nanopore-sequencing-of-samples-from-the-1000-genomes-project-to-build-a-comprehensive-catalog-of-human-genetic-variation/) - Fewer than half of individuals with a suspected Mendelian or monogenic condition receive a precise molecular diagnosis after comprehensive clinical genetic testing. Improvements in data quality and costs have heightened interest in using long-read sequencing (LRS) to streamline clinical genomic testing, but the absence of control data sets for variant filtering and prioritization has made - [Increased frequency of repeat expansion mutations across different populations](https://kidsfirstdrc.org/publication/increased-frequency-of-repeat-expansion-mutations-across-different-populations/) - Repeat expansion disorders (REDs) are a devastating group of predominantly neurological diseases. Together they are common, affecting 1 in 3,000 people worldwide with population-specific differences. However, prevalence estimates of REDs are hampered by heterogeneous clinical presentation, variable geographic distributions and technological limitations leading to underascertainment. Here, leveraging whole-genome sequencing data from 82,176 individuals from different - [A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank](https://kidsfirstdrc.org/publication/a-phenome-wide-association-study-of-tandem-repeat-variation-in-168554-individuals-from-the-uk-biobank/) - Most genetic association studies focus on binary variants. To identify the effects of multi-allelic variation of tandem repeats (TRs) on human traits, we perform direct TR genotyping and phenome-wide association studies in 168,554 individuals from the UK Biobank, identifying 47 TRs showing fine-mapped associations with 73 traits. We replicate 23 of 31 (74%) of these - [A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma](https://kidsfirstdrc.org/publication/a-proteogenomic-surfaceome-study-identifies-dlk1-as-an-immunotherapeutic-target-in-neuroblastoma/) - Cancer immunotherapies produce remarkable results in B cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor and normal tissues to identify biologically relevant cell surface immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer. Proteogenomic analyses reveal sixty high-confidence candidate - [Integration of transcriptomics and long-read genomics prioritizes structural variants in rare disease](https://kidsfirstdrc.org/publication/integration-of-transcriptomics-and-long-read-genomics-prioritizes-structural-variants-in-rare-disease/) - Rare structural variants (SVs)-insertions, deletions, and complex rearrangements-can cause Mendelian disease, yet they remain difficult to accurately detect and interpret. We sequenced and analyzed Oxford Nanopore Technologies long-read genomes of 68 individuals from the undiagnosed disease network (UDN) with no previously identified diagnostic mutations from short-read sequencing. Using our optimized SV detection pipelines and 571 - [Variability in proliferative and migratory defects in Hirschsprung disease-associated RET pathogenic variants](https://kidsfirstdrc.org/publication/variability-in-proliferative-and-migratory-defects-in-hirschsprung-disease-associated-ret-pathogenic-variants/) - Hirschsprung disease (HSCR) exhibits extensive genetic heterogeneity, with 72% of cases involving pathogenic variants in 10 genes forming a gene regulatory network (GRN) essential for enteric nervous system (ENS) development. The receptor tyrosine kinase gene RET is the most significant contributor, implicated in 12%-50% of individuals depending on the phenotype. RET plays a critical role - [Genetic association analysis of 77,539 genomes reveals rare disease etiologies.](https://kidsfirstdrc.org/publication/genetic-association-analysis-of-77539-genomes-reveals-rare-disease-etiologies/) - The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the 'Rareservoir', containing the rare variant genotypes and phenotypes of 77,539 participants - [Rare germline structural variants increase risk for pediatric solid tumors](https://kidsfirstdrc.org/publication/rare-germline-structural-variants-increase-risk-for-pediatric-solid-tumors/) - Pediatric solid tumors are a leading cause of childhood disease mortality. In this work, we examined germline structural variants (SVs) as risk factors for pediatric extracranial solid tumors using germline genome sequencing of 1765 affected children, their 943 unaffected parents, and 6665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline - [MAGEL2-related disorders: A study and case series.](https://kidsfirstdrc.org/publication/magel2-related-disorders-a-study-and-case-series/) - Pathogenic MAGEL2 variants result in the phenotypes of Chitayat-Hall syndrome (CHS), Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). We present five patients with mutations in MAGEL2, including the first patient reported with a missense variant, adding to the limited literature. Further, we performed a systematic review of the CHS and SYS literature, assess the overlap - [Interrogating Causal Effects of Body Composition and Puberty-Related Risk Factors on Adolescent Idiopathic Scoliosis: A Two-Sample Mendelian Randomization Study.](https://kidsfirstdrc.org/publication/interrogating-causal-effects-of-body-composition-and-puberty-related-risk-factors-on-adolescent-idiopathic-scoliosis-a-two-sample-mendelian-randomization-study/) - Adolescent idiopathic scoliosis (AIS) is the most common form of pediatric musculoskeletal disorder. Observational studies have pointed to several risk factors for AIS, but almost no evidence exists to support their causal association with AIS. Here, we applied Mendelian randomization (MR), known to limit bias from confounding and reverse causation, to investigate causal associations between - [Jasmine and Iris: population-scale structural variant comparison and analysis.](https://kidsfirstdrc.org/publication/jasmine-and-iris-population-scale-structural-variant-comparison-and-analysis/) - The availability of long reads is revolutionizing studies of structural variants (SVs). However, because SVs vary across individuals and are discovered through imprecise read technologies and methods, they can be difficult to compare. Addressing this, we present Jasmine and Iris ( https://github.com/mkirsche/Jasmine/ ), for fast and accurate SV refinement, comparison and population analysis. Using an - [MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance.](https://kidsfirstdrc.org/publication/macf1-mutations-encoding-highly-conserved-zinc-binding-residues-of-the-gar-domain-cause-defects-in-neuronal-migration-and-axon-guidance/) - To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as - [Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders.](https://kidsfirstdrc.org/publication/mutations-in-the-u4-snrna-gene-rnu4-2-cause-one-of-the-most-prevalent-monogenic-neurodevelopmental-disorders/) - Most people with intellectual disability (ID) do not receive a molecular diagnosis following genetic testing. To identify new etiologies of ID, we performed a genetic association analysis comparing the burden of rare variants in 41,132 noncoding genes between 5,529 unrelated cases and 46,401 unrelated controls. RNU4-2, which encodes U4 small nuclear RNA, a critical component - [Network assisted analysis of de novo variants using protein-protein interaction information identified 46 candidate genes for congenital heart disease.](https://kidsfirstdrc.org/publication/network-assisted-analysis-of-de-novo-variants-using-protein-protein-interaction-information-identified-46-candidate-genes-for-congenital-heart-disease/) - De novo variants (DNVs) with deleterious effects have proved informative in identifying risk genes for early-onset diseases such as congenital heart disease (CHD). A number of statistical methods have been proposed for family-based studies or case/control studies to identify risk genes by screening genes with more DNVs than expected by chance in Whole Exome Sequencing - [Pan-African genome demonstrates how population-specific genome graphs improve high-throughput sequencing data analysis.](https://kidsfirstdrc.org/publication/pan-african-genome-demonstrates-how-population-specific-genome-graphs-improve-high-throughput-sequencing-data-analysis/) - Graph-based genome reference representations have seen significant development, motivated by the inadequacy of the current human genome reference to represent the diverse genetic information from different human populations and its inability to maintain the same level of accuracy for non-European ancestries. While there have been many efforts to develop computationally efficient graph-based toolkits for NGS - [Phenotype delineation of ZNF462 related syndrome.](https://kidsfirstdrc.org/publication/phenotype-delineation-of-znf462-related-syndrome/) - Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants - [Pleiotropy method reveals genetic overlap between orofacial clefts at multiple novel loci from GWAS of multi-ethnic trios.](https://kidsfirstdrc.org/publication/pleiotropy-method-reveals-genetic-overlap-between-orofacial-clefts-at-multiple-novel-loci-from-gwas-of-multi-ethnic-trios/) - Based on epidemiologic and embryologic patterns, nonsyndromic orofacial clefts- the most common craniofacial birth defects in humans- are commonly categorized into cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which are traditionally considered to be etiologically distinct. However, some evidence of shared genetic risk in IRF6, GRHL3 and ARHGAP29 regions - [Quantifying concordant genetic effects of de novo mutations on multiple disorders.](https://kidsfirstdrc.org/publication/quantifying-concordant-genetic-effects-of-de-novo-mutations-on-multiple-disorders/) - Exome sequencing on tens of thousands of parent-proband trios has identified numerous deleterious de novo mutations (DNMs) and implicated risk genes for many disorders. Recent studies have suggested shared genes and pathways are enriched for DNMs across multiple disorders. However, existing analytic strategies only focus on genes that reach statistical significance for multiple disorders and - [Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?](https://kidsfirstdrc.org/publication/rare-variants-found-in-multiplex-families-with-orofacial-clefts-does-expanding-the-phenotype-make-a-difference/) - Exome sequencing (ES) is now a relatively straightforward process to identify causal variants in Mendelian disorders. However, the same is not true for ES in families where the inheritance patterns are less clear, and a complex etiology is suspected. Orofacial clefts (OFCs) are highly heritable birth defects with both Mendelian and complex etiologies. The phenotypic - [Rare variants in the endocytic pathway are associated with Alzheimer's disease, its related phenotypes, and functional consequences.](https://kidsfirstdrc.org/publication/rare-variants-in-the-endocytic-pathway-are-associated-with-alzheimers-disease-its-related-phenotypes-and-functional-consequences/) - Late-onset Alzheimer's disease (LOAD) is the most common type of dementia causing irreversible brain damage to the elderly and presents a major public health challenge. Clinical research and genome-wide association studies have suggested a potential contribution of the endocytic pathway to AD, with an emphasis on common loci. However, the contribution of rare variants in - [Secondary Genome-Wide Association Study Using Novel Analytical Strategies Disentangle Genetic Components of Cleft Lip and/or Cleft Palate in 1q32.2.](https://kidsfirstdrc.org/publication/secondary-genome-wide-association-study-using-novel-analytical-strategies-disentangle-genetic-components-of-cleft-lip-and-or-cleft-palate-in-1q32-2/) - Orofacial cleft (OFC) is one of the most prevalent birth defects, leading to substantial and long-term burdens in a newborn's quality of life. Although studies revealed several genetic variants associated with the birth defect, novel approaches may provide additional clues about its etiology. Using the Center for Craniofacial and Dental Genetics project data (n = - [The influence of genetics in congenital diaphragmatic hernia.](https://kidsfirstdrc.org/publication/the-influence-of-genetics-in-congenital-diaphragmatic-hernia/) - Congenital diaphragmatic hernia (CDH) is a common birth defect that is associated with significant morbidity and mortality, especially when associated with additional congenital anomalies. Both environmental and genetic factors are thought to contribute to CDH. The genetic contributions to CDH are highly heterogeneous and incompletely defined. No one genetic cause accounts for more than 1-2% - [Statistical methods for assessing the effects of de novo variants on birth defects.](https://kidsfirstdrc.org/publication/statistical-methods-for-assessing-the-effects-of-de-novo-variants-on-birth-defects/) - With the development of next-generation sequencing technology, de novo variants (DNVs) with deleterious effects can be identified and investigated for their effects on birth defects such as congenital heart disease (CHD). However, statistical power is still limited for such studies because of the small sample size due to the high cost of recruiting and sequencing - [Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.](https://kidsfirstdrc.org/publication/genomic-analyses-in-cornelia-de-lange-syndrome-and-related-diagnoses-novel-candidate-genes-genotype-phenotype-correlations-and-common-mechanisms/) - Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major - [Identification of USP9X as a leukemia susceptibility gene.](https://kidsfirstdrc.org/publication/identification-of-usp9x-as-a-leukemia-susceptibility-gene/) - We recently reported that children with multiple birth defects have a significantly higher risk of childhood cancer. We performed whole-genome sequencing on a cohort of probands from this study with birth defects and cancer and their parents. Structural variant analysis identified a novel 5 kb de novo heterozygous inframe deletion overlapping the catalytic domain of - [Microscopic examination of spatial transcriptome using Seq-Scope.](https://kidsfirstdrc.org/publication/microscopic-examination-of-spatial-transcriptome-using-seq-scope/) - Spatial barcoding technologies have the potential to reveal histological details of transcriptomic profiles; however, they are currently limited by their low resolution. Here, we report Seq-Scope, a spatial barcoding technology with a resolution comparable to an optical microscope. Seq-Scope is based on a solid-phase amplification of randomly barcoded single-molecule oligonucleotides using an Illumina sequencing platform. - [Predicting functional effect of missense variants using graph attention neural networks.](https://kidsfirstdrc.org/publication/predicting-functional-effect-of-missense-variants-using-graph-attention-neural-networks/) - Accurate prediction of damaging missense variants is critically important for interpreting a genome sequence. Although many methods have been developed, their performance has been limited. Recent advances in machine learning and the availability of large-scale population genomic sequencing data provide new opportunities to considerably improve computational predictions. Here we describe the graphical missense variant pathogenicity - [Rare variants regulate expression of nearby individual genes in multiple tissues.](https://kidsfirstdrc.org/publication/rare-variants-regulate-expression-of-nearby-individual-genes-in-multiple-tissues/) - The rapid decrease in sequencing cost has enabled genetic studies to discover rare variants associated with complex diseases and traits. Once this association is identified, the next step is to understand the genetic mechanism of rare variants on how the variants influence diseases. Similar to the hypothesis of common variants, rare variants may affect diseases - [Representing glycophenotypes: semantic unification of glycobiology resources for disease discovery.](https://kidsfirstdrc.org/publication/representing-glycophenotypes-semantic-unification-of-glycobiology-resources-for-disease-discovery/) - While abnormalities related to carbohydrates (glycans) are frequent for patients with rare and undiagnosed diseases as well as in many common diseases, these glycan-related phenotypes (glycophenotypes) are not well represented in knowledge bases (KBs). If glycan-related diseases were more robustly represented and curated with glycophenotypes, these could be used for molecular phenotyping to help to - [STtools: A Comprehensive Software Pipeline for Ultra-high Resolution Spatial Transcriptomics Data.](https://kidsfirstdrc.org/publication/sttools-a-comprehensive-software-pipeline-for-ultra-high-resolution-spatial-transcriptomics-data/) - Motivation: While there are many software pipelines for analyzing spatial transcriptomics data, few can process ultra high-resolution datasets generated by emerging technologies. There is a clear need for new software tools that can handle sub-micrometer resolution spatial transcriptomics data with computational scalability without compromising its resolution. - [Systematic evaluation of genome sequencing for the diagnostic assessment of autism spectrum disorder and fetal structural anomalies.](https://kidsfirstdrc.org/publication/systematic-evaluation-of-genome-sequencing-for-the-diagnostic-assessment-of-autism-spectrum-disorder-and-fetal-structural-anomalies/) - Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility of GS, we - [Template-based prediction of protein structure with deep learning.](https://kidsfirstdrc.org/publication/template-based-prediction-of-protein-structure-with-deep-learning/) - Background: Accurate prediction of protein structure is fundamentally important to understand biological function of proteins. Template-based modeling, including protein threading and homology modeling, is a popular method for protein tertiary structure prediction. However, accurate template-query alignment and template selection are still very challenging, especially for the proteins with only distant homologs available. - [Ten lessons for data sharing with a data commons.](https://kidsfirstdrc.org/publication/ten-lessons-for-data-sharing-with-a-data-commons/) - A data commons is a cloud-based data platform with a governance structure that allows a community to manage, analyze and share its data. Data commons provide a research community with the ability to manage and analyze large datasets using the elastic scalability provided by cloud computing and to share data securely and compliantly, and, in - [The Biomedical Research Hub: a federated platform for patient research data.](https://kidsfirstdrc.org/publication/the-biomedical-research-hub-a-federated-platform-for-patient-research-data/) - Objective: The objective was to develop and operate a cloud-based federated system for managing, analyzing, and sharing patient data for research purposes, while allowing each resource sharing patient data to operate their component based upon their own governance rules. The federated system is called the Biomedical Research Hub (BRH). - [The genetic overlap between osteoporosis and craniosynostosis.](https://kidsfirstdrc.org/publication/the-genetic-overlap-between-osteoporosis-and-craniosynostosis/) - Osteoporosis is the most prevalent bone condition in the ageing population. This systemic disease is characterized by microarchitectural deterioration of bone, leading to increased fracture risk. In the past 15 years, genome-wide association studies (GWAS), have pinpointed hundreds of loci associated with bone mineral density (BMD), helping elucidate the underlying molecular mechanisms and genetic architecture - [The Genomics Research and Innovation Network: creating an interoperable, federated, genomics learning system.](https://kidsfirstdrc.org/publication/the-genomics-research-and-innovation-network-creating-an-interoperable-federated-genomics-learning-system/) - Purpose: Clinicians and researchers must contextualize a patient's genetic variants against population-based references with detailed phenotyping. We sought to establish globally scalable technology, policy, and procedures for sharing biosamples and associated genomic and phenotypic data on broadly consented cohorts, across sites of care. - [The Human Phenotype Ontology in 2024: phenotypes around the world.](https://kidsfirstdrc.org/publication/the-human-phenotype-ontology-in-2024-phenotypes-around-the-world/) - The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort - [The landscape of human SVA retrotransposons.](https://kidsfirstdrc.org/publication/the-landscape-of-human-sva-retrotransposons/) - SINE-VNTR-Alu (SVA) retrotransposons are evolutionarily young and still-active transposable elements (TEs) in the human genome. Several pathogenic SVA insertions have been identified that directly mutate host genes to cause neurodegenerative and other types of diseases. However, due to their sequence heterogeneity and complex structures as well as limitations in sequencing techniques and analysis, SVA insertions - [The Pediatric Cell Atlas: Defining the Growth Phase of Human Development at Single-Cell Resolution.](https://kidsfirstdrc.org/publication/the-pediatric-cell-atlas-defining-the-growth-phase-of-human-development-at-single-cell-resolution/) - Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles - [Towards self-describing and FAIR bulk formats for biomedical data.](https://kidsfirstdrc.org/publication/towards-self-describing-and-fair-bulk-formats-for-biomedical-data/) - We introduce a self-describing serialized format for bulk biomedical data called the Portable Format for Biomedical (PFB) data. The Portable Format for Biomedical data is based upon Avro and encapsulates a data model, a data dictionary, the data itself, and pointers to third party controlled vocabularies. In general, each data element in the data dictionary - [Imipridones affect tumor bioenergetics and promote cell lineage differentiation in diffuse midline gliomas.](https://kidsfirstdrc.org/publication/imipridones-affect-tumor-bioenergetics-and-promote-cell-lineage-differentiation-in-diffuse-midline-gliomas/) - Background: Pediatric diffuse midline gliomas (DMGs) are incurable childhood cancers. The imipridone ONC201 has shown early clinical efficacy in a subset of DMGs. However, the anticancer mechanisms of ONC201 and its derivative ONC206 have not been fully described in DMGs. - [Informatics Methods and Infrastructure Needed to Study Factors Associated with High Incidence of Pediatric Brain and Central Nervous System Tumors in Kentucky.](https://kidsfirstdrc.org/publication/informatics-methods-and-infrastructure-needed-to-study-factors-associated-with-high-incidence-of-pediatric-brain-and-central-nervous-system-tumors-in-kentucky/) - Pediatric brain and central nervous system tumors (PBCNSTs) are the most common solid tumors and are the leading cause of disease-related death in US children. PBCNST incidence rates in Kentucky are significantly higher than in the United States as a whole, and are even higher among Kentucky's Appalachian children. To understand and eventually eliminate such - [Novel ATXN1/ATXN1L::NUTM2A fusions identified in aggressive infant sarcomas with gene expression and methylation patterns similar to CIC-rearranged sarcoma.](https://kidsfirstdrc.org/publication/novel-atxn1-atxn1lnutm2a-fusions-identified-in-aggressive-infant-sarcomas-with-gene-expression-and-methylation-patterns-similar-to-cic-rearranged-sarcoma/) - CIC-rearranged sarcomas are newly defined undifferentiated soft tissue tumors with CIC-associated fusions, and dismal prognosis. CIC fusions activate PEA3 family genes, ETV1/4/5, leading to tumorigenesis and progression. We report two high-grade CNS sarcomas of unclear histological diagnosis and one disseminated tumor of unknown origin with novel fusions and similar gene-expression/methylation patterns without CIC rearrangement. All - [NTRK Fusions Identified in Pediatric Tumors: The Frequency, Fusion Partners, and Clinical Outcome.](https://kidsfirstdrc.org/publication/ntrk-fusions-identified-in-pediatric-tumors-the-frequency-fusion-partners-and-clinical-outcome/) - Purpose: Neurotrophic tyrosine receptor kinase (NTRK) fusions have been described as oncogenic drivers in a variety of tumors. However, little is known about the overall frequency of NTRK fusion in unselected pediatric tumors. Here, we assessed the frequency, fusion partners, and clinical course in pediatric patients with NTRK fusion-positive tumors. - [Potential Role of IFNγ Inhibition in Refractory Cytokine Release Syndrome Associated with CAR T-cell Therapy.](https://kidsfirstdrc.org/publication/potential-role-of-ifnγ-inhibition-in-refractory-cytokine-release-syndrome-associated-with-car-t-cell-therapy/) - Here we review the pathophysiology and management of cytokine release syndrome (CRS) secondary to immunotherapy, and potential options for CRS refractory to IL6 inhibition and glucocorticoids, for which there are no proven treatments. To illustrate, we describe a patient with B-cell acute lymphoblastic leukemia who developed refractory grade 4 CRS following CD19-directed chimeric antigen receptor - [Rational drug combinations with CDK4/6 inhibitors in acute lymphoblastic leukemia.](https://kidsfirstdrc.org/publication/rational-drug-combinations-with-cdk4-6-inhibitors-in-acute-lymphoblastic-leukemia/) - Despite improvements in outcomes for children with B- and T-cell acute lymphoblastic leukemia (B-ALL and T-ALL), patients with resistant or relapsed disease fare poorly. Previous studies have demonstrated the essential role of cyclin D3 in T-ALL disease initiation and progression and that targeting of the CDK4/6-cyclin D complex can suppress T-ALL proliferation, leading to efficient - [Role of non-chromosomal birth defects on the risk of developing childhood Hodgkin lymphoma: A Children's Oncology Group study.](https://kidsfirstdrc.org/publication/role-of-non-chromosomal-birth-defects-on-the-risk-of-developing-childhood-hodgkin-lymphoma-a-childrens-oncology-group-study/) - Background: Non-chromosomal birth defects are an important risk factor for several childhood cancers. However, these associations are less clear for Hodgkin lymphoma (HL). Therefore, we sought to more fully elucidate the association between non-chromosomal birth defects and HL risk. - [SOHO State of the Art Updates and Next Questions | Novel Approaches to Pediatric T-cell ALL and T-Lymphoblastic Lymphoma.](https://kidsfirstdrc.org/publication/soho-state-of-the-art-updates-and-next-questions-novel-approaches-to-pediatric-t-cell-all-and-t-lymphoblastic-lymphoma/) - While outcomes for children with T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LL) have improved significantly with contemporary therapy, outcomes for patients with relapsed or refractory (r/r) disease remain dismal. Improved risk stratification and the incorporation of novel therapeutics have the potential to improve outcomes further in T-ALL/T-LL by limiting relapse risk and improving - [Somatic structural variation signatures in pediatric brain tumors.](https://kidsfirstdrc.org/publication/somatic-structural-variation-signatures-in-pediatric-brain-tumors/) - Brain cancer is the leading cause of cancer-related death in children. Somatic structural variations (SVs), large-scale alterations in DNA, remain poorly understood in pediatric brain tumors. Here, we detect a total of 13,199 high-confidence somatic SVs in 744 whole-genome sequences of pediatric brain tumors from the Pediatric Brain Tumor Atlas. The somatic SV occurrences have - [Taking a BiTE Out of CAR-T Cell Efficacy.](https://kidsfirstdrc.org/publication/taking-a-bite-out-of-car-t-cell-efficacy/) - #N/A - [Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models.](https://kidsfirstdrc.org/publication/transcriptional-and-functional-consequences-of-alterations-to-mef2c-and-its-topological-organization-in-neuronal-models/) - Point mutations and structural variants that directly disrupt the coding sequence of MEF2C have been associated with a spectrum of neurodevelopmental disorders (NDDs). However, the impact of MEF2C haploinsufficiency on neurodevelopmental pathways and synaptic processes is not well understood, nor are the complex mechanisms that govern its regulation. To explore the functional changes associated with - [VBASS enables integration of single cell gene expression data in Bayesian association analysis of rare variants.](https://kidsfirstdrc.org/publication/vbass-enables-integration-of-single-cell-gene-expression-data-in-bayesian-association-analysis-of-rare-variants/) - Rare or de novo variants have substantial contribution to human diseases, but the statistical power to identify risk genes by rare variants is generally low due to rarity of genotype data. Previous studies have shown that risk genes usually have high expression in relevant cell types, although for many conditions the identity of these cell - [Generation of synthetic whole-slide image tiles of tumours from RNA-sequencing data via cascaded diffusion models.](https://kidsfirstdrc.org/publication/generation-of-synthetic-whole-slide-image-tiles-of-tumours-from-rna-sequencing-data-via-cascaded-diffusion-models/) - Training machine-learning models with synthetically generated data can alleviate the problem of data scarcity when acquiring diverse and sufficiently large datasets is costly and challenging. Here we show that cascaded diffusion models can be used to synthesize realistic whole-slide image tiles from latent representations of RNA-sequencing data from human tumours. Alterations in gene expression affected - [Intra-tumoral T cells in pediatric brain tumors display clonal expansion and effector properties.](https://kidsfirstdrc.org/publication/intra-tumoral-t-cells-in-pediatric-brain-tumors-display-clonal-expansion-and-effector-properties/) - Brain tumors in children are a devastating disease in a high proportion of patients. Owing to inconsistent results in clinical trials in unstratified patients, the role of immunotherapy remains unclear. We performed an in-depth survey of the single-cell transcriptomes and clonal relationship of intra-tumoral T cells from children with brain tumors. Our results demonstrate that - [The children's brain tumor network (CBTN) - Accelerating research in pediatric central nervous system tumors through collaboration and open science.](https://kidsfirstdrc.org/publication/the-childrens-brain-tumor-network-cbtn-accelerating-research-in-pediatric-central-nervous-system-tumors-through-collaboration-and-open-science/) - Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created - [The Genetics of Neurodevelopment in Congenital Heart Disease.](https://kidsfirstdrc.org/publication/the-genetics-of-neurodevelopment-in-congenital-heart-disease/) - Congenital heart disease (CHD) is the most common birth anomaly, affecting almost 1% of infants. Neurodevelopmental delay is the most common extracardiac feature in people with CHD. Many factors may contribute to neurodevelopmental risk, including genetic factors, CHD physiology, and the prenatal/postnatal environment. Damaging variants are most highly enriched among individuals with extracardiac anomalies or - [NCI Cancer Research Data Commons: Lessons Learned and Future State.](https://kidsfirstdrc.org/publication/nci-cancer-research-data-commons-lessons-learned-and-future-state/) - More than ever, scientific progress in cancer research hinges on our ability to combine datasets and extract meaningful interpretations to better understand diseases and ultimately inform the development of better treatments and diagnostic tools. To enable the successful sharing and use of big data, the NCI developed the Cancer Research Data Commons (CRDC), providing access - [Identification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations With Atrial Fibrillation.](https://kidsfirstdrc.org/publication/identification-of-functional-genetic-determinants-of-cardiac-troponin-t-and-i-in-a-multiethnic-population-and-causal-associations-with-atrial-fibrillation/) - Background: Elevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive. - [Germline microsatellite genotypes differentiate children with medulloblastoma.](https://kidsfirstdrc.org/publication/germline-microsatellite-genotypes-differentiate-children-with-medulloblastoma/) - Background: The germline genetic events underpinning medulloblastoma (MB) initiation, and therefore the ability to determine who is at risk, are still unknown for the majority of cases. Microsatellites are short repeated sequences that make up ~3% of the genome. Repeat lengths vary among individuals and are often nonrandomly associated with disease, including several cancers such - [Genomic characterization of a PPP1CB-ALK fusion with fusion gene amplification in a congenital glioblastoma.](https://kidsfirstdrc.org/publication/genomic-characterization-of-a-ppp1cb-alk-fusion-with-fusion-gene-amplification-in-a-congenital-glioblastoma/) - ALK (Anaplastic lymphoma kinase) fusion proteins are oncogenic and have been seen in various tumors. PPP1CB-ALK fusions are rare but have been reported in a few patients with low- or high-grade gliomas. However, little is known regarding the mechanism of fusion formation and genomic break points of this fusion. We performed genomic characterization of a - [Genomic analysis and preclinical xenograft model development identify potential therapeutic targets for MYOD1-mutant soft-tissue sarcoma of childhood.](https://kidsfirstdrc.org/publication/genomic-analysis-and-preclinical-xenograft-model-development-identify-potential-therapeutic-targets-for-myod1-mutant-soft-tissue-sarcoma-of-childhood/) - The myogenic differentiation 1 gene (MYOD1) p.L122R somatic mutation was first discovered in a subset of clinically aggressive embryonal rhabdomyosarcomas and has since been described in both pediatric and adult spindle cell/sclerosing rhabdomyosarcomas. Relatively little is known about the clinical, molecular, and histopathological features of these tumors in children. In order to further characterize the - [Genome-Wide Association Study Identifies a Susceptibility Locus for Comitant Esotropia and Suggests a Parent-of-Origin Effect.](https://kidsfirstdrc.org/publication/genome-wide-association-study-identifies-a-susceptibility-locus-for-comitant-esotropia-and-suggests-a-parent-of-origin-effect/) - Purpose: To identify genetic variants conferring susceptibility to esotropia. Esotropia is the most common form of comitant strabismus, has its highest incidence in European ancestry populations, and is believed to be inherited as a complex trait. - [Genetic models and approaches to study orofacial clefts.](https://kidsfirstdrc.org/publication/genetic-models-and-approaches-to-study-orofacial-clefts/) - Introduction: Orofacial clefts (OFCs) are common craniofacial birth defects with heterogeneous phenotype and etiology. Geneticists have applied nearly every available method and technology for further understanding of the genetic architectures of OFCs. - [Gene-based analyses of the maternal genome implicate maternal effect genes as risk factors for conotruncal heart defects.](https://kidsfirstdrc.org/publication/gene-based-analyses-of-the-maternal-genome-implicate-maternal-effect-genes-as-risk-factors-for-conotruncal-heart-defects/) - Congenital heart defects (CHDs) affect approximately 1% of newborns. Epidemiological studies have identified several genetically-mediated maternal phenotypes (e.g., pregestational diabetes, chronic hypertension) that are associated with the risk of CHDs in offspring. However, the role of the maternal genome in determining CHD risk has not been defined. We present findings from gene-level, genome-wide studies that - [GATK-gCNV enables the discovery of rare copy number variants from exome sequencing data.](https://kidsfirstdrc.org/publication/gatk-gcnv-enables-the-discovery-of-rare-copy-number-variants-from-exome-sequencing-data/) - Copy number variants (CNVs) are major contributors to genetic diversity and disease. While standardized methods, such as the genome analysis toolkit (GATK), exist for detecting short variants, technical challenges have confounded uniform large-scale CNV analyses from whole-exome sequencing (WES) data. Given the profound impact of rare and de novo coding CNVs on genome organization and - [Expectations and blind spots for structural variation detection from long-read assemblies and short-read genome sequencing technologies.](https://kidsfirstdrc.org/publication/expectations-and-blind-spots-for-structural-variation-detection-from-long-read-assemblies-and-short-read-genome-sequencing-technologies/) - Virtually all genome sequencing efforts in national biobanks, complex and Mendelian disease programs, and medical genetic initiatives are reliant upon short-read whole-genome sequencing (srWGS), which presents challenges for the detection of structural variants (SVs) relative to emerging long-read WGS (lrWGS) technologies. Given this ubiquity of srWGS in large-scale genomics initiatives, we sought to establish expectations - [Disease-associated c-MYC downregulation in human disorders of transcriptional regulation.](https://kidsfirstdrc.org/publication/disease-associated-c-myc-downregulation-in-human-disorders-of-transcriptional-regulation/) - Cornelia de Lange syndrome (CdLS) is a rare multiorgan developmental disorder caused by pathogenic variants in cohesin genes. It is a genetically and clinically heterogeneous dominant (both autosomal and X-linked) rare disease. Increasing experimental evidence indicates that CdLS is caused by a combination of factors, such as gene expression dysregulation, accumulation of cellular damage and - [Development and Clinical Validation of a Large Fusion Gene Panel for Pediatric Cancers.](https://kidsfirstdrc.org/publication/development-and-clinical-validation-of-a-large-fusion-gene-panel-for-pediatric-cancers/) - Gene fusions are one of the most common genomic alterations in pediatric cancer. Many fusions encode oncogenic drivers and play important roles in cancer diagnosis, risk stratification, and treatment selection. We report the development and clinical validation of a large custom-designed RNA sequencing panel, CHOP Fusion panel, using anchored multiplex PCR technology. The panel interrogates - [Detecting Gene-Environment Interaction for Maternal Exposures Using Case-Parent Trios Ascertained Through a Case With Non-Syndromic Orofacial Cleft.](https://kidsfirstdrc.org/publication/detecting-gene-environment-interaction-for-maternal-exposures-using-case-parent-trios-ascertained-through-a-case-with-non-syndromic-orofacial-cleft/) - Two large studies of case-parent trios ascertained through a proband with a non-syndromic orofacial cleft (OFC, which includes cleft lip and palate, cleft lip alone, or cleft palate alone) were used to test for possible gene-environment (G × E) interaction between genome-wide markers (both observed and imputed) and self-reported maternal exposure to smoking, alcohol consumption, - [Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita.](https://kidsfirstdrc.org/publication/deleterious-de-novo-variants-of-x-linked-zc4h2-in-females-cause-a-variable-phenotype-with-neurogenic-arthrogryposis-multiplex-congenita/) - Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 - [Decreased ACKR3 (CXCR7) function causes oculomotor synkinesis in mice and humans.](https://kidsfirstdrc.org/publication/decreased-ackr3-cxcr7-function-causes-oculomotor-synkinesis-in-mice-and-humans/) - Oculomotor synkinesis is the involuntary movement of the eyes or eyelids with a voluntary attempt at a different movement. The chemokine receptor CXCR4 and its ligand CXCL12 regulate oculomotor nerve development; mice with loss of either molecule have oculomotor synkinesis. In a consanguineous family with congenital ptosis and elevation of the ptotic eyelid with ipsilateral - [De novo structural mutation rates and gamete-of-origin biases revealed through genome sequencing of 2,396 families.](https://kidsfirstdrc.org/publication/de-novo-structural-mutation-rates-and-gamete-of-origin-biases-revealed-through-genome-sequencing-of-2396-families/) - Each human genome includes de novo mutations that arose during gametogenesis. While these germline mutations represent a fundamental source of new genetic diversity, they can also create deleterious alleles that impact fitness. Whereas the rate and patterns of point mutations in the human germline are now well understood, far less is known about the frequency - [Contribution of Previously Unrecognized RNA Splice-Altering Variants to Congenital Heart Disease.](https://kidsfirstdrc.org/publication/contribution-of-previously-unrecognized-rna-splice-altering-variants-to-congenital-heart-disease/) - Background: Known genetic causes of congenital heart disease (CHD) explain - [Comprehensive Serum Proteome Profiling of Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome Patients with B-Cell ALL Receiving CAR T19.](https://kidsfirstdrc.org/publication/comprehensive-serum-proteome-profiling-of-cytokine-release-syndrome-and-immune-effector-cell-associated-neurotoxicity-syndrome-patients-with-b-cell-all-receiving-car-t19/) - Purpose: To study the biology and identify markers of severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in children after chimeric antigen receptor T-cell (CAR T) treatment. - [Comprehensive identification of transposable element insertions using multiple sequencing technologies.](https://kidsfirstdrc.org/publication/comprehensive-identification-of-transposable-element-insertions-using-multiple-sequencing-technologies/) - Transposable elements (TEs) help shape the structure and function of the human genome. When inserted into some locations, TEs may disrupt gene regulation and cause diseases. Here, we present xTea (x-Transposable element analyzer), a tool for identifying TE insertions in whole-genome sequencing data. Whereas existing methods are mostly designed for short-read data, xTea can be - [Closing in on Mechanisms of Open Neural Tube Defects.](https://kidsfirstdrc.org/publication/closing-in-on-mechanisms-of-open-neural-tube-defects/) - Neural tube defects (NTDs) represent a failure of the neural plate to complete the developmental transition to a neural tube. NTDs are the most common birth anomaly of the CNS. Following mandatory folic acid fortification of dietary grains, a dramatic reduction in the incidence of NTDs was observed in areas where the policy was implemented, - [Clinically Relevant and Minimally Invasive Tumor Surveillance of Pediatric Diffuse Midline Gliomas Using Patient-Derived Liquid Biopsy.](https://kidsfirstdrc.org/publication/clinically-relevant-and-minimally-invasive-tumor-surveillance-of-pediatric-diffuse-midline-gliomas-using-patient-derived-liquid-biopsy/) - Purpose: Pediatric diffuse midline glioma (DMG) are highly malignant tumors with poor clinical outcomes. Over 70% of patients with DMG harbor the histone 3 p.K27M (H3K27M) mutation, which correlates with a poorer clinical outcome, and is also used as a criterion for enrollment in clinical trials. Because complete surgical resection of DMG is not an - [Children's Oncology Group's 2023 blueprint for research: Epidemiology.](https://kidsfirstdrc.org/publication/childrens-oncology-groups-2023-blueprint-for-research-epidemiology/) - The Children's Oncology Group (COG) Epidemiology Committee has a primary focus on better understanding the etiologies of childhood cancers. Over the past 10 years, the committee has leveraged the Childhood Cancer Research Network, and now more recently Project:EveryChild (PEC), to conduct epidemiologic assessments of various childhood cancers, including osteosarcoma, neuroblastoma, germ cell tumors, Ewing sarcoma, - [Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma.](https://kidsfirstdrc.org/publication/childrens-oncology-group-trial-aall1231-a-phase-iii-clinical-trial-testing-bortezomib-in-newly-diagnosed-t-cell-acute-lymphoblastic-leukemia-and-lymphoma/) - Purpose: To improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined in the Children's Oncology Group phase III clinical trial AALL1231, which also attempted to reduce the use of prophylactic cranial radiation (CRT) in newly diagnosed T-ALL. - [Central nervous system status is prognostic in T-cell acute lymphoblastic leukemia: a Children's Oncology Group report.](https://kidsfirstdrc.org/publication/central-nervous-system-status-is-prognostic-in-t-cell-acute-lymphoblastic-leukemia-a-childrens-oncology-group-report/) - To determine the prognostic significance of central nervous system (CNS) leukemic involvement in newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL), outcomes on consecutive, phase 3 Children's Oncology Group clinical trials were examined. AALL0434 and AALL1231 tested efficacy of novel agents within augmented-Berlin-Frankfurt-Münster (aBFM) therapy. In addition to testing study-specific chemotherapy through randomization, the AALL0434 regimen - [Cancer Informatics for Cancer Centers: Scientific Drivers for Informatics, Data Science, and Care in Pediatric, Adolescent, and Young Adult Cancer.](https://kidsfirstdrc.org/publication/cancer-informatics-for-cancer-centers-scientific-drivers-for-informatics-data-science-and-care-in-pediatric-adolescent-and-young-adult-cancer/) - Cancer Informatics for Cancer Centers (CI4CC) is a grassroots, nonprofit 501c3 organization intended to provide a focused national forum for engagement of senior cancer informatics leaders, primarily aimed at academic cancer centers anywhere in the world but with a special emphasis on the 70 National Cancer Institute-funded cancer centers. This consortium has regularly held topic-focused - [AutoGVP: a dockerized workflow integrating ClinVar and InterVar germline sequence variant classification.](https://kidsfirstdrc.org/publication/autogvp-a-dockerized-workflow-integrating-clinvar-and-intervar-germline-sequence-variant-classification/) - Summary: With the increasing rates of exome and whole genome sequencing, the ability to classify large sets of germline sequencing variants using up-to-date American College of Medical Genetics-Association for Molecular Pathology (ACMG-AMP) criteria is crucial. Here, we present Automated Germline Variant Pathogenicity (AutoGVP), a tool that integrates germline variant pathogenicity annotations from ClinVar and sequence - [Associations between birth defects with neural crest cell origins and pediatric embryonal tumors.](https://kidsfirstdrc.org/publication/associations-between-birth-defects-with-neural-crest-cell-origins-and-pediatric-embryonal-tumors/) - Background: There are few assessments evaluating associations between birth defects with neural crest cell developmental origins (BDNCOs) and embryonal tumors, which are characterized by undifferentiated cells having a molecular profile similar to neural crest cells. The effect of BDNCOs on embryonal tumors was estimated to explore potential shared etiologic pathways and genetic origins. - [annoFuse: an R Package to annotate, prioritize, and interactively explore putative oncogenic RNA fusions.](https://kidsfirstdrc.org/publication/annofuse-an-r-package-to-annotate-prioritize-and-interactively-explore-putative-oncogenic-rna-fusions/) - Background: Gene fusion events are significant sources of somatic variation across adult and pediatric cancers and are some of the most clinically-effective therapeutic targets, yet low consensus of RNA-Seq fusion prediction algorithms makes therapeutic prioritization difficult. In addition, events such as polymerase read-throughs, mis-mapping due to gene homology, and fusions occurring in healthy normal tissue - [An efficient linear mixed model framework for meta-analytic association studies across multiple contexts.](https://kidsfirstdrc.org/publication/an-efficient-linear-mixed-model-framework-for-meta-analytic-association-studies-across-multiple-contexts/) - Linear mixed models (LMMs) can be applied in the meta-analyses of responses from individuals across multiple contexts, increasing power to detect associations while accounting for confounding effects arising from within-individual variation. However, traditional approaches to fitting these models can be computationally intractable. Here, we describe an efficient and exact method for fitting a multiple-context linear - [Accurate in silico confirmation of rare copy number variant calls from exome sequencing data using transfer learning.](https://kidsfirstdrc.org/publication/accurate-in-silico-confirmation-of-rare-copy-number-variant-calls-from-exome-sequencing-data-using-transfer-learning/) - Exome sequencing is widely used in genetic studies of human diseases and clinical genetic diagnosis. Accurate detection of copy number variants (CNVs) is important to fully utilize exome sequencing data. However, exome data are noisy. None of the existing methods alone can achieve both high precision and recall rate. A common practice is to perform - [Accurate diagnosis of atopic dermatitis by combining transcriptome and microbiota data with supervised machine learning.](https://kidsfirstdrc.org/publication/accurate-diagnosis-of-atopic-dermatitis-by-combining-transcriptome-and-microbiota-data-with-supervised-machine-learning/) - Atopic dermatitis (AD) is a common skin disease in childhood whose diagnosis requires expertise in dermatology. Recent studies have indicated that host genes-microbial interactions in the gut contribute to human diseases including AD. We sought to develop an accurate and automated pipeline for AD diagnosis based on transcriptome and microbiota data. Using these data of - [A Practical Guide for Structural Variation Detection in the Human Genome.](https://kidsfirstdrc.org/publication/a-practical-guide-for-structural-variation-detection-in-the-human-genome/) - Profiling genetic variants-including single nucleotide variants, small insertions and deletions, copy number variations, and structural variations (SVs)-from both healthy individuals and individuals with disease is a key component of genetic and biomedical research. SVs are large-scale changes in the genome and involve breakage and rejoining of DNA fragments. They may affect thousands to millions of - [A germline PALB2 pathogenic variant identified in a pediatric high-grade glioma.](https://kidsfirstdrc.org/publication/a-germline-palb2-pathogenic-variant-identified-in-a-pediatric-high-grade-glioma/) - PALB2 (partner and localizer of BRCA2) gene encodes a protein that colocalizes with BRCA2 in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2PALB2 plays a critical role in maintaining genome integrity through its role in the Fanconi anemia and homologous recombination DNA repair pathways. It has a known loss-of-function disease - [A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3.](https://kidsfirstdrc.org/publication/a-genome-wide-association-study-of-nonsyndromic-cleft-palate-identifies-an-etiologic-missense-variant-in-grhl3/) - Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk - [A Deep Intronic PKHD1 Variant Identified by SpliceAI in a Deceased Neonate With Autosomal Recessive Polycystic Kidney Disease.](https://kidsfirstdrc.org/publication/a-deep-intronic-pkhd1-variant-identified-by-spliceai-in-a-deceased-neonate-with-autosomal-recessive-polycystic-kidney-disease/) - The etiologies of newborn deaths in neonatal intensive care units usually remain unknown, even after genetic testing. Whole-genome sequencing, combined with artificial intelligence-based methods for predicting the effects of non-coding variants, provide an avenue for resolving these deaths. Using one such method, SpliceAI, we identified a maternally inherited deep intronic PKHD1 splice variant (chr6:52030169T>C), in - [A cross-disorder dosage sensitivity map of the human genome.](https://kidsfirstdrc.org/publication/a-cross-disorder-dosage-sensitivity-map-of-the-human-genome/) - Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million - [AXIN1 mutations in nonsyndromic craniosynostosis.](https://kidsfirstdrc.org/publication/axin1-mutations-in-nonsyndromic-craniosynostosis/) - Objective: Occurring once in every 2000 live births, craniosynostosis (CS) is the most frequent cranial birth defect. Although the genetic etiologies of syndromic CS cases are well defined, the genetic cause of most nonsyndromic cases remains unknown. - [High Comorbidity of Pediatric Cancers in Patients with Birth Defects: Insights from Whole Genome Sequencing Analysis of Copy Number Variations.](https://kidsfirstdrc.org/publication/high-comorbidity-of-pediatric-cancers-in-patients-with-birth-defects-insights-from-whole-genome-sequencing-analysis-of-copy-number-variations/) - Background: Patients with birth defects (BD) exhibit an elevated risk of cancer. We aimed to investigate the potential link between pediatric cancers and BDs, exploring the hypothesis of shared genetic defects contributing to the coexistence of these conditions. - [Perinatal thymic-derived CD8αβ-expressing γδ T cells are innate IFN-γ producers that expand in IL-7R-STAT5B-driven neoplasms.](https://kidsfirstdrc.org/publication/perinatal-thymic-derived-cd8αβ-expressing-γδ-t-cells-are-innate-ifn-γ-producers-that-expand-in-il-7r-stat5b-driven-neoplasms/) - The contribution of γδ T cells to immune responses is associated with rapid secretion of interferon-γ (IFN-γ). Here, we show a perinatal thymic wave of innate IFN-γ-producing γδ T cells that express CD8αβ heterodimers and expand in preclinical models of infection and cancer. Optimal CD8αβ+ γδ T cell development is directed by low T cell - [Treating sex and gender differences as a continuous variable can improve precision cancer treatments.](https://kidsfirstdrc.org/publication/treating-sex-and-gender-differences-as-a-continuous-variable-can-improve-precision-cancer-treatments/) - Background: The significant sex and gender differences that exist in cancer mechanisms, incidence, and survival, have yet to impact clinical practice. One barrier to translation is that cancer phenotypes cannot be segregated into distinct male versus female categories. Instead, within this convenient but contrived dichotomy, male and female cancer phenotypes are highly overlapping and vary - [Risk of meningomyelocele mediated by the common 22q11.2 deletion.](https://kidsfirstdrc.org/publication/risk-of-meningomyelocele-mediated-by-the-common-22q11-2-deletion/) - Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk - [Regulatory elements in SEM1-DLX5-DLX6 (7q21.3) locus contribute to genetic control of coronal nonsyndromic craniosynostosis and bone density-related traits.](https://kidsfirstdrc.org/publication/regulatory-elements-in-sem1-dlx5-dlx6-7q21-3-locus-contribute-to-genetic-control-of-coronal-nonsyndromic-craniosynostosis-and-bone-density-related-traits/) - Purpose: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown. - [Investigating gene functions and single-cell expression profiles of de novo variants in orofacial clefts.](https://kidsfirstdrc.org/publication/investigating-gene-functions-and-single-cell-expression-profiles-of-de-novo-variants-in-orofacial-clefts/) - Orofacial clefts (OFCs) are common congenital birth defects with various etiologies, including genetic variants. Online Mendelian Inheritance in Man (OMIM) annotated several hundred genes involving OFCs. Furthermore, several hundreds of de novo variants (DNVs) have been identified from individuals with OFCs. Some DNVs are related to known OFC genes or pathways, but there are still - [ALK upregulates POSTN and WNT signaling to drive neuroblastoma](https://kidsfirstdrc.org/publication/alk-upregulates-postn-and-wnt-signaling-to-drive-neuroblastoma/) - Neuroblastoma is the most common extracranial solid tumor of childhood. While MYCN and mutant anaplastic lymphoma kinase (ALKF1174L) cooperate in tumorigenesis, how ALK contributes to tumor formation remains unclear. Here, we used a human stem cell-based model of neuroblastoma. Mis-expression of ALKF1174L and MYCN resulted in shorter latency compared to MYCN alone. MYCN tumors resembled adrenergic, - [Deciphering complex breakage-fusion-bridge genome rearrangements with Ambigram](https://kidsfirstdrc.org/publication/deciphering-complex-breakage-fusion-bridge-genome-rearrangements-with-ambigram/) - Breakage-fusion-bridge (BFB) is a complex rearrangement that leads to tumor malignancy. Existing models for detecting BFBs rely on the ideal BFB hypothesis, ruling out the possibility of BFBs entangled with other structural variations, that is, complex BFBs. We propose an algorithm Ambigram to identify complex BFB and reconstruct the rearranged structure of the local genome - [Neuroblastoma and Glioblastoma Cases With Amplified Oncogenes Have Reduced Numbers of Tumor-Resident Adaptive Immune Receptor Recombinations](https://kidsfirstdrc.org/publication/neuroblastoma-and-glioblastoma-cases-with-amplified-oncogenes-have-reduced-numbers-of-tumor-resident-adaptive-immune-receptor-recombinations/) - Purpose: In certain cancers, oncogene amplification is correlated with an immunologically cold or noninflamed, tumor immune microenvironment (TIME) and a worse prognosis, for example, in the case of MYCN-amplified neuroblastoma (NBL). However, for other cancer types, the relationship between oncogene amplification and immune response is more complicated or unresolved. One such cancer is glioblastoma multiforme - [Functional dissection of human cardiac enhancers and noncoding de novo variants in congenital heart disease](https://kidsfirstdrc.org/publication/functional-dissection-of-human-cardiac-enhancers-and-noncoding-de-novo-variants-in-congenital-heart-disease/) - Rare coding mutations cause ∼45% of congenital heart disease (CHD). Noncoding mutations that perturb cis-regulatory elements (CREs) likely contribute to the remaining cases, but their identification has been problematic. Using a lentiviral massively parallel reporter assay (lentiMPRA) in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we functionally evaluated 6,590 noncoding de novo variants (ncDNVs) prioritized - [Rare variant modifier analysis identifies variants in SEC24D associated with orofacial cleft subtypes](https://kidsfirstdrc.org/publication/rare-variant-modifier-analysis-identifies-variants-in-sec24d-associated-with-orofacial-cleft-subtypes-2/) - As one of the most common structural birth defects, orofacial clefts (OFCs) have been studied for decades, and recent studies have demonstrated that there are genetic differences between the different phenotypic presentations of OFCs. However, the contribution of rare genetic variation genome-wide to different subtypes of OFCs has been understudied, with most studies focusing on - [Joint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape](https://kidsfirstdrc.org/publication/joint-multi-ancestry-and-admixed-gwas-reveals-the-complex-genetics-behind-human-cranial-vault-shape/) - The cranial vault in humans is highly variable, clinically relevant, and heritable, yet its genetic architecture remains poorly understood. Here, we conduct a joint multi-ancestry and admixed multivariate genome-wide association study on 3D cranial vault shape extracted from magnetic resonance images of 6772 children from the ABCD study cohort yielding 30 genome-wide significant loci. Follow-up - [PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects](https://kidsfirstdrc.org/publication/pls3-missense-variants-affecting-the-actin-binding-domains-cause-x-linked-congenital-diaphragmatic-hernia-and-body-wall-defects/) - Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin - [Transcriptional immunogenomic analysis reveals distinct immunological clusters in paediatric nervous system tumours](https://kidsfirstdrc.org/publication/transcriptional-immunogenomic-analysis-reveals-distinct-immunological-clusters-in-paediatric-nervous-system-tumours/) - Background: Cancer immunotherapies including immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR) T-cell therapy have shown variable response rates in paediatric patients highlighting the need to establish robust biomarkers for patient selection. While the tumour microenvironment in adults has been widely studied to delineate determinants of immune response, the immune composition of paediatric solid tumours - [Using existing pediatric cancer data from the Gabriella Miller Kids First Data Resource Program](https://kidsfirstdrc.org/publication/using-existing-pediatric-cancer-data-from-the-gabriella-miller-kids-first-data-resource-program/) - Childhood cancer and birth defects are leading causes of childhood mortality, and studies suggest that birth defects increase pediatric cancer risk. The Gabriella Miller Kids First Pediatric Research Program (Kids First) seeks to alleviate these conditions by building an expansive resource of genetic and clinical data from patients with pediatric cancer and birth defects and - [An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations](https://kidsfirstdrc.org/publication/an-ancient-founder-mutation-located-between-robo1-and-robo2-is-responsible-for-increased-microtia-risk-in-amerindigenous-populations/) - Microtia is a congenital malformation that encompasses mild hypoplasia to complete loss of the external ear, or pinna. Although the contribution of genetic variation and environmental factors to microtia remains elusive, Amerindigenous populations have the highest reported incidence. Here, using both transmission disequilibrium tests and association studies in microtia trios (parents and affected child) and - [Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastoma](https://kidsfirstdrc.org/publication/immunogenomic-determinants-of-tumor-microenvironment-correlate-with-superior-survival-in-high-risk-neuroblastoma/) - Background: Tumor-infiltrating CD8+ T cells and neoantigens are predictors of a favorable prognosis and response to immunotherapy with checkpoint inhibitors in many types of adult cancer, but little is known about their role in pediatric malignancies. Here, we analyzed the prognostic strength of T cell-inflamed gene expression and neoantigen load in high-risk neuroblastoma. We also - [Pervasive cis effects of variation in copy number of large tandem repeats on local DNA methylation and gene expression](https://kidsfirstdrc.org/publication/pervasive-cis-effects-of-variation-in-copy-number-of-large-tandem-repeats-on-local-dna-methylation-and-gene-expression/) - Variable number tandem repeats (VNTRs) are composed of large tandemly repeated motifs, many of which are highly polymorphic in copy number. However, because of their large size and repetitive nature, they remain poorly studied. To investigate the regulatory potential of VNTRs, we used read-depth data from Illumina whole-genome sequencing to perform association analysis between copy - [Systems biology analysis for Ewing sarcoma](https://kidsfirstdrc.org/publication/systems-biology-analysis-for-ewing-sarcoma/) - Ewing sarcoma (EwS) is a highly aggressive pediatric bone cancer that is defined by a somatic fusion between the EWSR1 gene and an ETS family member, most frequently the FLI1 gene, leading to expression of a chimeric transcription factor EWSR1-FLI1. Otherwise, EwS is one of the most genetically stable cancers. The situation when the major - [Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene](https://kidsfirstdrc.org/publication/rare-and-de-novo-variants-in-827-congenital-diaphragmatic-hernia-probands-implicate-lonp1-as-candidate-risk-gene/) - Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent - [trioPhaser: using Mendelian inheritance logic to improve genomic phasing of trios](https://kidsfirstdrc.org/publication/triophaser-using-mendelian-inheritance-logic-to-improve-genomic-phasing-of-trios/) - Background: When analyzing DNA sequence data of an individual, knowing which nucleotide was inherited from each parent can be beneficial when trying to identify certain types of DNA variants. Mendelian inheritance logic can be used to accurately phase (haplotype) the majority (67-83%) of an individual's heterozygous nucleotide positions when genotypes are available for both parents - [A survey of compound heterozygous variants in pediatric cancers and structural birth defects](https://kidsfirstdrc.org/publication/a-survey-of-compound-heterozygous-variants-in-pediatric-cancers-and-structural-birth-defects/) - Compound heterozygous (CH) variants occur when two recessive alleles are inherited and the variants are located at different loci within the same gene in a given individual. CH variants are important contributors to many different types of recessively inherited diseases. However, many studies overlook CH variants because identification of this type of variant requires knowing - [Selective modulation of a pan-essential protein as a therapeutic strategy in cancer](https://kidsfirstdrc.org/publication/selective-modulation-of-a-pan-essential-protein-as-a-therapeutic-strategy-in-cancer/) - Cancer dependency maps, which use CRISPR/Cas9 depletion screens to profile the landscape of genetic dependencies in hundreds of cancer cell lines, have identified context-specific dependencies that could be therapeutically exploited. An ideal therapy is both lethal and precise, but these depletion screens cannot readily distinguish between gene effects that are cytostatic or cytotoxic. Here, we - [Effective variant filtering and expected candidate variant yield in studies of rare human disease](https://kidsfirstdrc.org/publication/effective-variant-filtering-and-expected-candidate-variant-yield-in-studies-of-rare-human-disease/) - In studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore - [Haploinsufficiency of SF3B2 causes craniofacial microsomia](https://kidsfirstdrc.org/publication/haploinsufficiency-of-sf3b2-causes-craniofacial-microsomia/) - Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10-10), a - [A survey of rare epigenetic variation in 23,116 human genomes identifies disease-relevant epivariations and CGG expansions](https://kidsfirstdrc.org/publication/a-survey-of-rare-epigenetic-variation-in-23116-human-genomes-identifies-disease-relevant-epivariations-and-cgg-expansions/) - There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles - [Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21](https://kidsfirstdrc.org/publication/whole-genome-sequencing-of-orofacial-cleft-trios-from-the-gabriella-miller-kids-first-pediatric-research-consortium-identifies-a-new-locus-on-chromosome-21/) - Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families - [Genome-wide enrichment of de novo coding mutations in orofacial cleft trios](https://kidsfirstdrc.org/publication/genome-wide-enrichment-of-de-novo-coding-mutations-in-orofacial-cleft-trios/) - Although de novo mutations (DNMs) are known to increase an individual's risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs - [Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes](https://kidsfirstdrc.org/publication/likely-damaging-de-novo-variants-in-congenital-diaphragmatic-hernia-patients-are-associated-with-worse-clinical-outcomes/) - Purpose: Congenital diaphragmatic hernia (CDH) is associated with significant mortality and long-term morbidity in some but not all individuals. We hypothesize monogenic factors that cause CDH are likely to have pleiotropic effects and be associated with worse clinical outcomes. Methods: We enrolled and prospectively followed 647 newborns with CDH and performed genomic sequencing on 462 - [Genomic analyses implicate noncoding de novo variants in congenital heart disease](https://kidsfirstdrc.org/publication/genomic-analyses-implicate-noncoding-de-novo-variants-in-congenital-heart-disease/) - A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of - [Deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias](https://kidsfirstdrc.org/publication/deep-whole-genome-sequencing-of-multiple-proband-tissues-and-parental-blood-reveals-the-complex-genetic-etiology-of-congenital-diaphragmatic-hernias/) - The diaphragm is critical for respiration and separation of the thoracic and abdominal cavities, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDH), a common and often lethal birth defect. The genetic etiology of CDH is complex. Single-nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs) in more than 150 genes - [Elucidation of de novo small insertion/deletion biology with parent‐of‐origin phasing](https://kidsfirstdrc.org/publication/elucidation-of-de-novo-small-insertion-deletion-biology-with-parent‐of‐origin-phasing/) - The mechanisms underlying de novo insertion/deletion (indel) genesis, such as polymerase slippage, have been hypothesized but not well characterized in the human genome. We implemented two methodological improvements, which were leveraged to dissect indel mutagenesis. We assigned de novo variants to parent-of-origin (i.e., phasing) with low-coverage long-read whole-genome sequencing, achieving better phasing compared to short-read - [Germline 16p11. 2 microdeletion predisposes to neuroblastoma](https://kidsfirstdrc.org/publication/germline-16p11-2-microdeletion-predisposes-to-neuroblastoma/) - Neuroblastoma is a cancer of the developing sympathetic nervous system. It is diagnosed in 600-700 children per year in the United States and accounts for 12% of pediatric cancer deaths. Despite recent advances in our understanding of this malignancy's complex genetic architecture, the contribution of rare germline variants remains undefined. Here, we conducted a genome-wide - [ORE identifies extreme expression effects enriched for rare variants](https://kidsfirstdrc.org/publication/ore-identifies-extreme-expression-effects-enriched-for-rare-variants/) - Motivation: Non-coding rare variants (RVs) may contribute to Mendelian disorders but have been challenging to study due to small sample sizes, genetic heterogeneity and uncertainty about relevant non-coding features. Previous studies identified RVs associated with expression outliers, but varying outlier definitions were employed and no comprehensive open-source software was developed. Results: We developed Outlier-RV Enrichment - [De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders](https://kidsfirstdrc.org/publication/de-novo-variants-in-congenital-diaphragmatic-hernia-identify-myrf-as-a-new-syndrome-and-reveal-genetic-overlaps-with-other-developmental-disorders/) - Congenital diaphragmatic hernia (CDH) is a severe birth defect that is often accompanied by other congenital anomalies. Previous exome sequencing studies for CDH have supported a role of de novo damaging variants but did not identify any recurrently mutated genes. To investigate further the genetics of CDH, we analyzed de novo coding variants in 362 - [Identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas](https://kidsfirstdrc.org/publication/identification-and-validation-of-candidate-risk-genes-in-endocytic-vesicular-trafficking-associated-with-esophageal-atresia-and-tracheoesophageal-fistulas/) - Esophageal atresias/tracheoesophageal fistulas (EA/TEF) are rare congenital anomalies caused by aberrant development of the foregut. Previous studies indicate that rare or de novo genetic variants significantly contribute to EA/TEF risk, and most individuals with EA/TEF do not have pathogenic genetic variants in established risk genes. To identify the genetic contributions to EA/TEF, we performed whole - [Neither cardiac mitochondrial DNA variation nor copy number contribute to congenital heart disease risk](https://kidsfirstdrc.org/publication/neither-cardiac-mitochondrial-dna-variation-nor-copy-number-contribute-to-congenital-heart-disease-risk/) - The well-established manifestation of mitochondrial mutations in functional cardiac disease (e.g., mitochondrial cardiomyopathy) prompted the hypothesis that mitochondrial DNA (mtDNA) sequence and/or copy number (mtDNAcn) variation contribute to cardiac defects in congenital heart disease (CHD). MtDNAcns were calculated and rare, non-synonymous mtDNA mutations were identified in 1,837 CHD-affected proband-parent trios, 116 CHD-affected singletons, and 114 - [Congenital heart defects caused by FOXJ1](https://kidsfirstdrc.org/publication/congenital-heart-defects-caused-by-foxj1/) - FOXJ1 is expressed in ciliated cells of the airways, testis, oviduct, central nervous system and the embryonic left-right organizer. Ablation or targeted mutation of Foxj1 in mice, zebrafish and frogs results in loss of ciliary motility and/or reduced length and number of motile cilia, affecting the establishment of the left-right axis. In humans, heterozygous pathogenic - [Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting](https://kidsfirstdrc.org/publication/rare-variants-found-in-clinical-gene-panels-illuminate-the-genetic-and-allelic-architecture-of-orofacial-clefting/) - Purpose: Orofacial clefts (OFCs) are common birth defects including cleft lip, cleft lip and palate, and cleft palate. OFCs have heterogeneous etiologies, complicating clinical diagnostics because it is not always apparent if the cause is Mendelian, environmental, or multifactorial. Sequencing is not currently performed for isolated or sporadic OFCs; therefore, we estimated the diagnostic yield - [Discovery of novel predisposing coding and noncoding variants in familial Hodgkin lymphoma](https://kidsfirstdrc.org/publication/discovery-of-novel-predisposing-coding-and-noncoding-variants-in-familial-hodgkin-lymphoma/) - Familial aggregation of Hodgkin lymphoma (HL) has been demonstrated in large population studies, pointing to genetic predisposition to this hematological malignancy. To understand the genetic variants associated with the development of HL, we performed whole genome sequencing on 234 individuals with and without HL from 36 pedigrees that had 2 or more first-degree relatives with - [Multi-ancestry genome-wide association study of 4069 children with glioma identifies 9p21. 3 risk locus](https://kidsfirstdrc.org/publication/multi-ancestry-genome-wide-association-study-of-4069-children-with-glioma-identifies-9p21-3-risk-locus/) - Background: Although recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric central nervous system tumors have been identified to date. Methods: Meta-analysis of 3 population-based genome-wide association studies comprising 4069 children with glioma - [Prioritization of non-coding elements involved in non-syndromic cleft lip with/without cleft palate through genome-wide analysis of de novo mutations](https://kidsfirstdrc.org/publication/prioritization-of-non-coding-elements-involved-in-non-syndromic-cleft-lip-with-without-cleft-palate-through-genome-wide-analysis-of-de-novo-mutations/) - Non-syndromic cleft lip with/without cleft palate (nsCL/P) is a highly heritable facial disorder. To date, systematic investigations of the contribution of rare variants in non-coding regions to nsCL/P etiology are sparse. Here, we re-analyzed available whole-genome sequence (WGS) data from 211 European case-parent trios with nsCL/P and identified 13,522 de novo mutations (DNMs) in nsCL/P - [Damaging variants in FOXI3 cause microtia and craniofacial microsomia](https://kidsfirstdrc.org/publication/damaging-variants-in-foxi3-cause-microtia-and-craniofacial-microsomia/) - Purpose: Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown. Methods: We performed genome sequencing and linkage analysis in patients and families with microtia and - [Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis](https://kidsfirstdrc.org/publication/noncoding-variants-alter-gata2-expression-in-rhombomere-4-motor-neurons-and-cause-dominant-hereditary-congenital-facial-paresis/) - Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes - [A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature](https://kidsfirstdrc.org/publication/a-mutational-hotspot-in-amotl1-defines-a-new-syndrome-of-orofacial-clefting-cardiac-anomalies-and-tall-stature/) - AMOTL1 encodes angiomotin-like protein 1, an actin-binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricular anomalies, and gastrointestinal manifestations in individuals - [Clinically actionable secondary findings in 130 triads from sub‐Saharan African families with non‐syndromic orofacial clefts](https://kidsfirstdrc.org/publication/clinically-actionable-secondary-findings-in-130-triads-from-sub‐saharan-african-families-with-non‐syndromic-orofacial-clefts/) - Introduction: The frequency and implications of secondary findings (SFs) from genomic testing data have been extensively researched. However, little is known about the frequency or reporting of SFs in Africans, who are underrepresented in large-scale population genomic studies. The availability of data from the first whole-genome sequencing for orofacial clefts in an African population motivated - [Integrative genomic analyses identify lncRNA regulatory networks across pediatric leukemias and solid tumors](https://kidsfirstdrc.org/publication/integrative-genomic-analyses-identify-lncrna-regulatory-networks-across-pediatric-leukemias-and-solid-tumors/) - Long noncoding RNAs (lncRNA) play an important role in gene regulation and contribute to tumorigenesis. While pan-cancer studies of lncRNA expression have been performed for adult malignancies, the lncRNA landscape across pediatric cancers remains largely uncharted. Here, we curated RNA sequencing data for 1,044 pediatric leukemia and extracranial solid tumors and integrated paired tumor whole - [Genome-wide evaluation of the effect of short tandem repeat variation on local DNA methylation](https://kidsfirstdrc.org/publication/genome-wide-evaluation-of-the-effect-of-short-tandem-repeat-variation-on-local-dna-methylation/) - Short tandem repeats (STRs) contribute significantly to genetic diversity in humans, including disease-causing variation. Although the effect of STR variation on gene expression has been extensively assessed, their impact on epigenetics has been poorly studied and limited to specific genomic regions. Here, we investigated the hypothesis that some STRs act as independent regulators of local - [Identification of risk variants related to malignant tumors in children with birth defects by whole genome sequencing.](https://kidsfirstdrc.org/publication/identification-of-risk-variants-related-to-malignant-tumors-in-children-with-birth-defects-by-whole-genome-sequencing/) - Background: Children with birth defects (BD) are more likely to develop cancer and the increased risk of cancer persists into adulthood. Prior population-based assessments have demonstrated that even non-chromosomal BDs are associated with at least two-fold increase of cancer risk. Identification of variants that are associated with malignant tumor in BD patients without chromosomal anomalies - [Cytosine base editing enables quadruple-edited allogeneic CART cells for T-ALL.](https://kidsfirstdrc.org/publication/cytosine-base-editing-enables-quadruple-edited-allogeneic-cart-cells-for-t-all/) - llogeneic chimeric antigen receptor T-cell (CART) therapies require multiple gene edits to be clinically tractable. Most allogeneic CARTs have been created using gene editing techniques that induce DNA double-stranded breaks (DSBs), resulting in unintended on-target editing outcomes with potentially unforeseen consequences. Cytosine base editors (CBEs) install C•G to T•A point mutations in T cells, with - [Whole-genome sequencing reveals de-novo mutations associated with nonsyndromic cleft lip/palate](https://kidsfirstdrc.org/publication/whole-genome-sequencing-reveals-de-novo-mutations-associated-with-nonsyndromic-cleft-lip-palate/) - The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact protein-altering DNMs that contribute to the risk of nsCL/P, we conducted whole-genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands - [Disruption of the HIF-1 pathway in individuals with Ollier disease and Maffucci syndrome](https://kidsfirstdrc.org/publication/disruption-of-the-hif-1-pathway-in-individuals-with-ollier-disease-and-maffucci-syndrome/) - Ollier disease (OD) and Maffucci Syndrome (MS) are rare disorders characterized by multiple enchondromas, commonly causing bone deformities, limb length discrepancies, and pathological fractures. MS is distinguished from OD by the development of vascular anomalies. Both disorders are cancer predisposition syndromes with malignancies developing in ~50% of the individuals with OD or MS. Somatic gain-of-function - [Polygenic risk scores of endo-phenotypes identify the effect of genetic background in congenital heart disease](https://kidsfirstdrc.org/publication/polygenic-risk-scores-of-endo-phenotypes-identify-the-effect-of-genetic-background-in-congenital-heart-disease/) - Congenital heart disease (CHD) is a rare structural defect that occurs in ∼1% of live births. Studies on CHD genetic architecture have identified pathogenic single-gene mutations in less than 30% of cases. Single-gene mutations often show incomplete penetrance and variable expressivity. Therefore, we hypothesize that genetic background may play a role in modulating disease expression. - [Germline predisposition to pediatric Ewing sarcoma is characterized by inherited pathogenic variants in DNA damage repair genes](https://kidsfirstdrc.org/publication/germline-predisposition-to-pediatric-ewing-sarcoma-is-characterized-by-inherited-pathogenic-variants-in-dna-damage-repair-genes/) - More knowledge is needed regarding germline predisposition to Ewing sarcoma to inform biological investigation and clinical practice. Here, we evaluated the enrichment of pathogenic germline variants in Ewing sarcoma relative to other pediatric sarcoma subtypes, as well as patterns of inheritance of these variants. We carried out European-focused and pan-ancestry case-control analyses to screen for - [The arginine methyltransferase Carm1 is necessary for heart development](https://kidsfirstdrc.org/publication/the-arginine-methyltransferase-carm1-is-necessary-for-heart-development/) - To discover genes implicated in human congenital disorders, we performed ENU mutagenesis in the mouse and screened for mutations affecting embryonic development. In this work, we report defects of heart development in mice homozygous for a mutation of coactivator-associated arginine methyltransferase 1 (Carm1). While Carm1 has been extensively studied, it has never been previously associated - [Identification of a novel gene signature for neuroblastoma differentiation using a Boolean implication network](https://kidsfirstdrc.org/publication/identification-of-a-novel-gene-signature-for-neuroblastoma-differentiation-using-a-boolean-implication-network/) - Although induction of differentiation represents an effective strategy for neuroblastoma treatment, the mechanisms underlying neuroblastoma differentiation are poorly understood. We generated a computational model of neuroblastoma differentiation consisting of interconnected gene clusters identified based on symmetric and asymmetric gene expression relationships. We identified a differentiation signature consisting of series of gene clusters comprised of 1251 - [Integrative analysis of transcriptome dynamics during human craniofacial development identifies candidate disease genes](https://kidsfirstdrc.org/publication/integrative-analysis-of-transcriptome-dynamics-during-human-craniofacial-development-identifies-candidate-disease-genes/) - Craniofacial disorders arise in early pregnancy and are one of the most common congenital defects. To fully understand how craniofacial disorders arise, it is essential to characterize gene expression during the patterning of the craniofacial region. To address this, we performed bulk and single-cell RNA-seq on human craniofacial tissue from 4-8 weeks post conception. Comparisons - [Genomic landscape of Down syndrome–associated acute lymphoblastic leukemia](https://kidsfirstdrc.org/publication/genomic-landscape-of-down-syndrome-associated-acute-lymphoblastic-leukemia/) - Trisomy 21, the genetic cause of Down syndrome (DS), is the most common congenital chromosomal anomaly. It is associated with a 20-fold increased risk of acute lymphoblastic leukemia (ALL) during childhood and results in distinctive leukemia biology. To comprehensively define the genomic landscape of DS-ALL, we performed whole-genome sequencing and whole-transcriptome sequencing (RNA-Seq) on 295 - [Germline pathogenic variants in neuroblastoma patients are enriched in BARD1 and predict worse survival](https://kidsfirstdrc.org/publication/germline-pathogenic-variants-in-neuroblastoma-patients-are-enriched-in-bard1-and-predict-worse-survival/) - Background: Neuroblastoma is an embryonal cancer of the developing sympathetic nervous system. The genetic contribution of rare pathogenic or likely pathogenic germline variants in patients without a family history remains unclear. Methods: Germline DNA sequencing was performed on 786 neuroblastoma patients. The frequency of rare cancer predisposition gene pathogenic or likely pathogenic variants in patients was compared ## Datasets - [Kids First: Whole genome sequencing studies of multiplex nonsyndromic cleft lip/palate families](https://kidsfirstdrc.org/dataset/kids-first-whole-genome-sequencing-studies-of-multiplex-nonsyndromic-cleft-lip-palate-families/) - [Kids First: Enchondromatoses](https://kidsfirstdrc.org/dataset/kids-first-enchondromatoses/) - [Kids First: Bladder extrophy, Epispadias, Complex](https://kidsfirstdrc.org/dataset/kids-first-bladder-extrophy-epispadias-complex/) - [Kids First: Congenital Diaphragmatic Hernia](https://kidsfirstdrc.org/dataset/kids-first-congenital-diaphragmatic-hernia/) - [Kids First: Congenital Heart Defects](https://kidsfirstdrc.org/dataset/kids-first-congenital-heart-defects/) - [Kids First: Ewing Sarcoma - Genetic Risk](https://kidsfirstdrc.org/dataset/kids-first-ewing-sarcoma-genetic-risk/) - [Kids First: Orofacial Cleft - European Ancestry](https://kidsfirstdrc.org/dataset/kids-first-orofacial-cleft-european-ancestry/) - [Kids First: Syndromic Cranial Dysinnervation](https://kidsfirstdrc.org/dataset/kids-first-syndromic-cranial-dysinnervation/) - [Kids First: Adolescent Idiopathic Scoliosis](https://kidsfirstdrc.org/dataset/kids-first-adolescent-idiopathic-scoliosis/) - [Kids First: Disorders of Sex Development](https://kidsfirstdrc.org/dataset/kids-first-disorders-of-sex-development/) - [Kids First: Orofacial Cleft - Latin American](https://kidsfirstdrc.org/dataset/kids-first-orofacial-cleft-latin-american/) - [Kids First: Neuroblastoma](https://kidsfirstdrc.org/dataset/kids-first-neuroblastoma/) - [Kids First: Familial Leukemia](https://kidsfirstdrc.org/dataset/kids-first-familial-leukemia/) - [Kids First: Orofacial Cleft - African and Asian Ancestry](https://kidsfirstdrc.org/dataset/kids-first-orofacial-cleft-african-and-asian-ancestry/) - [Kids First: Novel Cancer Susceptibility in Families (from BASIC3)](https://kidsfirstdrc.org/dataset/kids-first-novel-cancer-susceptibility-in-families-from-basic3/) - [Kids First: Osteosarcoma](https://kidsfirstdrc.org/dataset/kids-first-osteosarcoma/) - [Kids First: Craniofacial Microsomia](https://kidsfirstdrc.org/dataset/kids-first-craniofacial-microsomia/) - [Kids First: Kidney and Urinary Tract Defects](https://kidsfirstdrc.org/dataset/kids-first-kidney-and-urinary-tract-defects/) - [Kids First: Microtia - Hispanic](https://kidsfirstdrc.org/dataset/kids-first-microtia-hispanic/) - [Kids First: Intersections of Cancer & SBD](https://kidsfirstdrc.org/dataset/kids-first-intersections-of-cancer-sbd/) - [Kids First: Esophageal Atresia and Tracheoesophageal Fistulas](https://kidsfirstdrc.org/dataset/kids-first-esophageal-atresia-and-tracheoesophageal-fistulas/) - [Kid First: Hemangiomas (PHACE)](https://kidsfirstdrc.org/dataset/kid-first-hemangiomas-phace/) - [Kids First: Nonsyndromic Craniosynostosis](https://kidsfirstdrc.org/dataset/kids-first-nonsyndromic-craniosynostosis/) - [Kids First: Myeloid Malignancies](https://kidsfirstdrc.org/dataset/kids-first-myeloid-malignancies/) - [Kids First: Leukemia & Heart Defects in Down Syndrome](https://kidsfirstdrc.org/dataset/kids-first-leukemia-heart-defects-in-down-syndrome/) - [Kids First: T-Cell ALL](https://kidsfirstdrc.org/dataset/kids-first-t-cell-all/) - [Kids First: Cornelia de Lange Syndrome](https://kidsfirstdrc.org/dataset/kids-first-cornelia-de-lange-syndrome/) - [Kids First: Laterality Birth Defects](https://kidsfirstdrc.org/dataset/kids-first-laterality-birth-defects/) - [Kids First: CHARGE Syndrome](https://kidsfirstdrc.org/dataset/kids-first-charge-syndrome/) - [Kids First: Orofacial Clefts - Philippines](https://kidsfirstdrc.org/dataset/kids-first-orofacial-clefts-philippines/) - [Kids First: Fetal Alcohol Spectrum Disorders](https://kidsfirstdrc.org/dataset/kids-first-fetal-alcohol-spectrum-disorders/) - [Kids First: Intracranial Germ Cell Tumors](https://kidsfirstdrc.org/dataset/kids-first-intracranial-germ-cell-tumors/) - [Kids First: Structural Defects of The Neural Tube](https://kidsfirstdrc.org/dataset/kids-first-structural-defects-of-the-neural-tube/) - [Kids First: Recessive Structural Brain Defects](https://kidsfirstdrc.org/dataset/kids-first-recessive-structural-brain-defects/) - [Kids First: Chromosome 18 Structural Birth Defects](https://kidsfirstdrc.org/dataset/kids-first-chromosome-18-structural-birth-defects/) - [Children's Brain Tumor Network (CBTN)](https://kidsfirstdrc.org/dataset/childrens-brain-tumor-network-cbtn/) ## Categories - [Articles](https://kidsfirstdrc.org/category/articles/) - [Events](https://kidsfirstdrc.org/category/events/) - [Press](https://kidsfirstdrc.org/category/press/) ## Tags - [Investigator Spotlight](https://kidsfirstdrc.org/tag/investigator-spotlight/) - [Foundation Spotlight](https://kidsfirstdrc.org/tag/foundation-spotlight/) - [CCDI](https://kidsfirstdrc.org/tag/ccdi/) - [Kids First](https://kidsfirstdrc.org/tag/kids-first/) - [CBTN](https://kidsfirstdrc.org/tag/cbtn/) - [PCDC](https://kidsfirstdrc.org/tag/pcdc/) - [St. Jude Cloud](https://kidsfirstdrc.org/tag/st-jude-cloud/) - [Treehouse Childhood Cancer Data Initiative](https://kidsfirstdrc.org/tag/treehouse-childhood-cancer-data-initiative/) - [National Cancer Institute](https://kidsfirstdrc.org/tag/national-cancer-institute/) - [data](https://kidsfirstdrc.org/tag/data/) - [Data federation](https://kidsfirstdrc.org/tag/data-federation/) - [childhood cancers](https://kidsfirstdrc.org/tag/childhood-cancers/) - [congenital disorders](https://kidsfirstdrc.org/tag/congenital-disorders/) - [Nara Sobreira](https://kidsfirstdrc.org/tag/nara-sobreira/) - [Angie Jelin](https://kidsfirstdrc.org/tag/angie-jelin/) - [Artificial intelligence](https://kidsfirstdrc.org/tag/artificial-intelligence/) - [childhood cancer](https://kidsfirstdrc.org/tag/childhood-cancer/) - [Gabriella Miller](https://kidsfirstdrc.org/tag/gabriella-miller/) - [Gabriella Miller Kids First Pediatric Research Program](https://kidsfirstdrc.org/tag/gabriella-miller-kids-first-pediatric-research-program/)