儿科癌症和结构性出生缺陷复合杂合变异的调查

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. 然而, many studies overlook CH variants because identification of this type of variant requires knowing the parent of origin for each nucleotide. Using computational methods, haplotypes can be inferred using a process called “phasing,” which estimates the chromosomal origin of most nucleotides. In this paper, we used germline, phased, whole-genome sequencing (全基因组测序) data to identify CH variants across seven pediatric diseases (青少年特发性脊柱侧凸: n = 16, 先天性心脏缺陷: n = 709, disorders of sex development: n = 79, ewing sarcoma: n = 287, 成神经细胞瘤: n = 259, orofacial cleft: n = 107, and syndromic cranial dysinnervation: n = 172), available as parent-child trios in the Gabriella Miller Kids First Data Resource Center. Relatively little is understood about the genetic underpinnings of these diseases. We classified CH variants as “potentially damaging” based on minor allele frequencies (MAF), Combined Annotation Dependent Depletion scores, variant impact on transcription or translation, and gene-level frequencies in the disease group compared to a healthy population. For comparison, we also identified homozygous alternate (HA) variants, which affect both gene copies at a single locus; HA variants represent an alternative mechanism of recessive disease development and do not require phasing. Across all diseases, 2.6% of the samples had a potentially damaging CH variant and 16.2% had a potentially damaging HA variant. Of these samples with potentially damaging variants, the average number of genes per sample was 1 with a CH variant and 1.25 with a HA variant. Across all samples, 5.1 genes per disease had a CH variant, while 35.6 genes per disease had a HA variant; on average, only 4.3% of these variants affected common genes. 所以, when seeking to identify potentially damaging variants of a putatively recessive disease, CH variants should be considered as potential contributors to disease development. If CH variants are excluded from analysis, important candidate genes may be overlooked.