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De novo variants are a common cause of genetic hearing loss

  • Miles J. Klimara
    Affiliations
    Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
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  • Carla Nishimura
    Affiliations
    Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
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  • Donghong Wang
    Affiliations
    Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
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  • Diana L. Kolbe
    Affiliations
    Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
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  • Amanda M. Schaefer
    Affiliations
    Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
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  • William D. Walls
    Affiliations
    Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
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  • Kathy L. Frees
    Affiliations
    Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
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  • Richard J.H. Smith
    Correspondence
    Correspondence and requests for materials should be addressed to Richard J.H. Smith, Molecular Otolaryngology and Renal Research Laboratories, Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 5270 Carver Biomedical Research Building, 285 Newton Road, Iowa City, IA 52242
    Affiliations
    Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
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  • Hela Azaiez
    Correspondence
    Hela Azaiez, Molecular Otolaryngology and Renal Research Laboratories, Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 5270 Carver Biomedical Research Building, 285 Newton Road, Iowa City, IA 52242.
    Affiliations
    Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
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Published:October 03, 2022DOI:https://doi.org/10.1016/j.gim.2022.08.028

      Abstract

      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 ∼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.

      Keywords

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