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De novo variants are a common cause of genetic hearing loss
Journal article   Open access   Peer reviewed

De novo variants are a common cause of genetic hearing loss

Miles J Klimara, Carla Nishimura, Donghong Wang, Diana L Kolbe, Amanda M Schaefer, William D Walls, Kathy L Frees, Richard J H Smith and Hela Azaiez
Genetics in medicine : official journal of the American College of Medical Genetics, Vol.24(12), pp.2555-2567
10/03/2022
DOI: 10.1016/j.gim.2022.08.028
PMCID: PMC9729384
PMID: 36194208
url
https://www.ncbi.nlm.nih.gov/pmc/articles/9729384View
Open Access

Abstract

PURPOSEDe 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. METHODSTargeted 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. RESULTSDNVs were detected in 10% (24/238) of trios for whom segregation analysis was performed. Overall, DNVs were causative in at least ∼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. CONCLUSIONDNVs are a relatively common cause of genetic HL and must be considered in all cases of sporadic HL.

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