De novo variants are a common cause of genetic hearing loss

Purpose: De novo variants (DNVs) are a well-recognized cause of genetic disorders. The contribution of DNVs to hearing loss (HL) is poorly characterized. We aimed to evaluate the rate of DNVs 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 DNVs in PubMed and ClinVar were reviewed to characterize the rate, distribution, and spectrum of DNVs in HL. Results: DNVs were detected in 10% (24/238) of trios for whom segregation analysis was performed. Overall, DNVs were causative in at least similar to 1% of probands for whom a genetic diagnosis was resolved, with marked variability based on inheritance mode and phenotype. DNVs of MITF were most common (21% of DNVs), followed by GATA3 (13%), STRC (13%), and ACTG1 (8%). Review of reported DNVs revealed gene-specific variability in contribution of DNV to the mutational spectrum of HL-associated genes. Conclusion: DNVs are a relatively common cause of genetic HL and must be considered in all cases of sporadic HL. (c) 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Automated summary

The study aimed to evaluate the occurrence rate of de novo variants (DNVs) in hearing loss-associated genes and assess their contribution to hearing loss. Through segregation analysis of a series of trio families, DNVs were found to be a relatively common cause of hearing loss, with marked variability based on inheritance mode and phenotype.