Integrative genetic and functional analysis of autosomal dominant hearing loss in 108 multigenerational families

Integrated strategy (targeted sequencing, linkage, genome, segregation, minigene) identifying coding and noncoding variants

A tiered strategy — targeted sequencing of 237 hearing-loss genes, genome-wide linkage, genome sequencing, segregation in 437 individuals, and minigene assays — was applied to 108 Polish families with confirmed autosomal dominant hearing loss. A molecular diagnosis was reached in 52% of families, with 67% of pathogenic variants previously unreported. The architecture was highly heterogeneous, with recurrent contributions from MYO6, TBC1D24, WFS1, GSDME, and POU4F3. Genome analyses revealed mechanisms beyond canonical coding regions, including the first deep intronic EYA4 variant associated with dominant hearing loss and a large 3'UTR deletion in ATP11A affecting alternative transcripts, both functionally confirmed.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This large, well-characterized and functionally validated European cohort is exactly the kind of study that advances noncoding variant interpretation. The first deep intronic EYA4 variant and the ATP11A 3'UTR deletion are reminders that the genome, not panel extension, is the horizon: these variants are only accessible via WGS coupled with RNA/minigene assays. The systematic integration of functional splicing assays is exemplary here.