Clinical application of whole exome sequencing (WES) in the genetic diagnosis of 768 Chinese patients with bilateral hearing loss.

Hearing loss is a prevalent sensory disability with strong genetic heterogeneity, affecting approximately 60% of patients due to genetic factors. To investigate the possible genetic causes of hearing loss in 768 unrelated Chinese patients and analyze the genetic diagnosis rates among patients with different clinical phenotypic characteristics, 768 patients were enrolled, and whole-exome sequencing (WES) was performed for genetic testing. Sanger sequencing, MLPA, or qPCR were used to verify the parental origin of identified variants. We identified possible genetic etiologies in 501 of the 768 patients (65.2%), including 456 with non-syndromic and 45 with syndromic hearing loss. A total of 214 variants from 30 genes were identified: 174 previously reported and 40 novel pathogenic/likely pathogenic variants, the 18 hotspot variants accounted for 71.9% of all identified variants. Notably, 15 patients carried de novo variants. The genetic diagnosis rate was significantly higher in patients with severe-profound hearing loss (95.8%, 474/495) compared to those with mild-moderate hearing loss (9.9%, 27/273), P < 0.001. Our findings expand the spectrum of genetic variants associated with hearing loss and demonstrate high genetic diagnosis rates in patients with severe-profound hearing loss and congenital onset. WES combined with parental origin verification is an effective and economical method for identifying the genetic etiology of hearing loss and can be considered a priority in clinical practice for guiding early intervention and preventing further hearing loss.