Análisis genómicos en el síndrome de Cornelia de Lange y diagnósticos relacionados: Nuevos genes candidatos, Correlaciones genotipo-fenotipo y mecanismos comunes..

Síndrome de Cornelia de Lange (SCdL) 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 pathogenic contributors to CdLS. Heterozygous or hemizygous
variants in the genes encoding these five proteins have been found to be
contributory to CdLS, with variants in NIPBL accounting for the majority
(>60%) of cases, and the only gene identified to date that results in the
severe or classic form of CdLS when mutated. Pathogenic variants in cohesin
genes other than NIPBL tend to result in a less severe phenotype. Causative
variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4,
can cause a CdLS-like phenotype. The common role that these genes, y
others, play as critical regulators of developmental transcriptional
control has led to the conditions they cause being referred to as disorders
of transcriptional regulation (o “DTRs”). Aquí, we report the results of a
comprehensive molecular analysis in a cohort of 716 probands with typical
and atypical CdLS in order to delineate the genetic contribution of
causative variants in cohesin complex genes as well as novel candidate
genes, genotype-phenotype correlations, and the utility of genome
sequencing in understanding the mutational landscape in this population.