Chromosomal Rearrangements Identified in Three Additional Patients With Generalized Congenital Hypertrichosis With...

We describe three unrelated individuals with congenital generalized hypertrichosis with gingival hyperplasia (CGHGH), each carrying a distinct structural rearrangement (duplication, deletion, inversion) at 17q24.2-q24.3 identified by CMA and WGS. Despite differences in the type of rearrangement, all three patients seem to exhibit alterations affecting the genomic architecture of a cluster of genes, particularly involving the ABCA family (notably ABCA5, ABCA6, ABCA9, ABCA10), MAP2K6, and potassium channels (KCNJ16, KCNJ2). These findings suggest that disruption of the local chromatin organization, including topologically associating domains (TADs), may contribute to the pathogenesis of CGHGH. Although previous studies implicated deletions affecting ABCA5 as the likely cause of CGHGH, our findings emphasize a broader spectrum of structural variation capable of producing similar phenotypes. Interestingly, one patient involved a cryptic 1.2 Mb inversion that disrupted the region between ABCA9 and KCNJ2, detectable only by whole genome sequencing, reinforcing the need for advanced molecular diagnostics in patients with syndromic hypertrichosis. In all three individuals, gingival overgrowth co-occurred with typical facial features, coarse hair, and normal cognitive development, adding evidence to the phenotype-genotype correlation. Overall, this study strengthens the hypothesis that disruption of regulatory elements and chromatin architecture at 17q24.2-q24.3, rather than single nucleotide variants alone, can be a primary driver of CGHGH. These findings underscore the need to incorporate genome-wide structural variant analysis in the diagnostic workflow of rare developmental disorders, especially those with heterogeneous or subtle clinical presentations.