Comprehensive Genetic Profiling of Sensorineural Hearing Loss Using an Integrative Diagnostic Approach

Despite the advent of Next-Generation Sequencing (NGS), genetic diagnosis of genetic disorders remains challenging, with diagnostic rates plateauing at approximately 50%. We investigated sensorineural hearing loss (SNHL), a prevalent sensory disorder with substantial genetic heterogeneity, through a comprehensive genomic analysis of a homogeneous disease cohort. Leveraging 394 families (750 individuals), we implemented a systematic multi-tiered genomic approach encompassing single-gene analysis to whole-genome sequencing (WGS), integrated with functional assays and bioinformatic analysis. Our methodological framework revealed a cumulative diagnostic yield of 55.6% (219 families), with automated WGS bioinformatics pipeline uncovering an additional 20 families harboring pathogenic variants, predominantly structural variants. Notably, comparative genomic analysis unveiled a higher frequency of single pathogenic alleles in recessive genes within our SNHL cohort relative to control populations. Subsequent deep intronic region interrogation identified three pathogenic variants on the opposite allele, substantiating the diagnostic utility of comprehensive genomic profiling. Through this approach, we delineated a genome-phenome landscape of SNHL, elucidating molecular signatures and establishing genotype-phenotype correlations at the inner ear functional level. This study underscores the transformative potential of WGS as a robust molecular diagnostic modality, advancing precision medicine paradigms in genetic disease research.