Complex Genomic Rearrangement Involving thePromoter Manifesting With Variable Expressivity in a Five-Generation Family.

Source: PubMed, NCBI / U.S. National Library of Medicine

Variants involvingare associated with ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension (ICPPS; also known as small patella syndrome), pulmonary arterial hypertension (PAH), and lethal lung developmental disorders. The variability of penetrance and expressivity ofvariants remains a prominent challenge in understanding their genotype-phenotype correlations. We investigated a five-generation family with 12 affected individuals presenting with isolated ICPPS, lung-related manifestations with features of ICPPS, and other milder abnormalities. Whole-genome sequencing was used to identify the causative and putative modifying variants. Wefound a complex genomic rearrangement (CGR) involving thepromoter and its 5 untranslated region that segregated in the family. This CGR consists of an ~38 bp insertion, an ~24 bp deletion, an ~2.4 kb deletion, and an ~235 bp inversion. Computational analyses in the proband's mother with pulmonary and skeletal manifestations revealed 27 candidate modifying noncoding SNVs in thelung-specific super-enhancer and 45 SNVs within its topologically associating domain (TAD), including seven variants within thepromoter. To explain the variable expressivity of this CGR, we propose that one or more of the variants within thelung-specific super-enhancer or TAD may act inwith the pathogenic CGR, modulatingexpression from the intact allele.