Seoul national university hospital, Korea, United States
Introduction: Sensorineural hearing loss (SNHL) is a common sensory disorder with a significant Mendelian genetic component, and despite comprehensive genetic testing like exome sequencing, about 50% of SNHL cases remain genetically unresolved, with the role of whole-genome sequencing (WGS) in diagnosing these cases not yet well established. This study aims to assess the diagnostic and clinical value of WGS in SNHL.
Methods: We investigated the genetic basis of SNHL in 394 families and 746 individuals, including probands (183, 46.2% male; median age 13, range 0-76) and their relatives. Collectively, we achieved a gradual improvement of diagnostic yield in the cohort, and complete genetic diagnosis (a pathogenic or likely pathogenic variant that explains the phenotype) was made in 219 families (55.58%). Among patients who remained undiagnosed, all syndromic SNHL patients and a representative subset of nonsyndromic SNHL patients were selected for WGS using a sample size estimation with a stratified sampling approach (n = 120).
Results: WGS identified causal variants in 23 of the 120 families (19.2%). Notably, 14 of these (11.7%) included deep intronic variants, small structural variants, and complex genomic rearrangements that were not detectable with previous methods. WGS proved most beneficial for patients with specific features such as early onset, syndromic characteristics, and those analyzed through trio-based WGS.
Conclusions: This study demonstrates that WGS can enhance the diagnostic yield for SNHL by approximately 12% beyond what is achieved with exome sequencing and other techniques. It confirms the clinical utility of WGS in diagnosing SNHL and highlights its potential in advancing precision medicine by providing a detailed genome-phenome landscape and uncovering genotype-phenotype correlations.
