Diagnostic yield of whole exome sequencing with targeted gene analysis in prelingual sensorineural hearing loss in...

Prelingual sensorineural hearing loss (SNHL) represents about 80% of genetic SNHL, with at least 90 causative genes identified. In order to identify the genetic diagnosis of prelingual SNHL, we performed a prospective study by systematic history-taking and phenotyping, followed by whole-exome sequencing (WES) with target gene analysis in 100 Thai patients. We found an overall diagnostic yield of 46%, 58.3% for familial cases, and 39.0% for sporadic cases. These included 41 cases with nonsyndromic SNHL(nsSNHL) and 5 cases with syndromic SNHL (sSNHL). We identified 41 P/LP and 4 VUS variants of 15 genes. Of those sSNHL, the causative genes were PAX3, SOX10, MITF (Waardenburg and Teitz syndromes), and SLC26A4 (Pendred syndrome). The genetic defects identified among those with nsSNHL were GJB2 and SLC26A4 as the most prevalent causes, followed by MYO15A, MYO7A, POU3F4, OTOF, PCDH15, GSDME, PTEN, ACTG1, TMPRSS3, MITF, and MPZL2. The inheritance of these nsSNHL genes involved X-linked recessive (n = 3), autosomal dominant (n = 3), and autosomal recessive in the remainder (n = 36). Patients with positive mutations underwent surveillance for associated symptoms like goiter and retinitis pigmentosa. In conclusion, most prelingual SNHL was nsSNHL with autosomal recessive inheritance. Identifying the causative gene benefits patients for specific management and genetic counseling.