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PURPOSE: De novo mutations (DNMs) are a well-recognized cause of genetic disorders. The contribution of DNMs to hearing loss (HL) is poorly characterized. We aimed to evaluate the rate of DNMs in HL-associated genes and assess their contribution to HL. METHODS: Targeted genomic enrichment and massively parallel sequencing were used for molecular testing of all exons and flanking intronic sequences of known HL-associated genes, with no exclusions on the basis of type of HL or clinical features. Segregation analysis was performed and previous reports of DNMs in PubMed and ClinVar were reviewed to characterize the rate, distribution, and spectrum of DNM in HL. RESULTS: DNMs were detected in 10% (24/238) of trios for whom segregation analysis was performed. Overall, DNMs were causative in at least ~1% of probands for which a genetic diagnosis was resolved, with marked variability based on inheritance mode and phenotype. DNMs of MITF were most common (21% of DNMs), followed by GATA3 (13%), STRC (13%), and ACTG1 (8%). Review of reported DNMs revealed gene-specific variability in contribution of DNM to the mutational spectrum of HL-associated genes. CONCLUSION: DNMs are a relatively common cause of genetic HL, and must be considered in all cases of sporadic HL.

We present detailed comparative analyses to assess population-level differences in patterns of genetic deafness between European/American and Japanese cohorts with non-syndromic hearing loss. One thousand eighty-three audiometric test results (921 European/American and 162 Japanese) from members of 168 families (48 European/American and 120 Japanese) with non-syndromic hearing loss secondary to pathogenic variants in one of three genes (KCNQ4, TECTA, WFS1) were studied. Audioprofile characteristics, specific mutation types, and protein domains were considered in the comparative analyses. Our findings support differences in audioprofiles driven by both mutation type (non-truncating vs. truncating) and ethnic background. The former finding confirms data that ascribe a phenotypic consequence to different mutation types in KCNQ4; the latter finding suggests that there are ethnic-specific effects (genetic and/or environmental) that impact gene-specific audioprofiles for TECTA and WFS1. Identifying the drivers of ethnic differences will refine our understanding of phenotype-genotype relationships and the biology of hearing and deafness.