Journal article
Genomic Landscape and Mutational Signatures of Deafness-Associated Genes
American journal of human genetics, Vol.103(4), pp.484-497
10/04/2018
DOI: 10.1016/j.ajhg.2018.08.006
PMCID: PMC6174355
PMID: 30245029
Abstract
The classification of genetic variants represents a major challenge in the post-genome era by virtue of their extraordinary number and the complexities associated with ascribing a clinical impact, especially for disorders exhibiting exceptional phenotypic, genetic, and allelic heterogeneity. To address this challenge for hearing loss, we have developed the Deafness Variation Database (DVD), a comprehensive, open-access resource that integrates all available genetic, genomic, and clinical data together with expert curation to generate a single classification for each variant in 152 genes implicated in syndromic and non-syndromic deafness. We evaluate 876,139 variants and classify them as pathogenic or likely pathogenic (more than 8,100 variants), benign or likely benign (more than 172,000 variants), or of uncertain significance (more than 695,000 variants); 1,270 variants are re-categorized based on expert curation and in 300 instances, the change is of medical significance and impacts clinical care. We show that more than 96% of coding variants are rare and novel and that pathogenicity is driven by minor allele frequency thresholds, variant effect, and protein domain. The mutational landscape we define shows complex gene-specific variability, making an understanding of these nuances foundational for improved accuracy in variant interpretation in order to enhance clinical decision making and improve our understanding of deafness biology.
Details
- Title: Subtitle
- Genomic Landscape and Mutational Signatures of Deafness-Associated Genes
- Creators
- Hela Azaiez - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAKevin T Booth - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USASean S Ephraim - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USABradley Crone - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAElizabeth A Black-Ziegelbein - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USARobert J Marini - Center for Bioinformatics and Computational Biology, Departments of Electrical and Computer Engineering and Biomedical Engineering, University of Iowa College of Engineering, Iowa City, IA 52242, USAA. Eliot Shearer - Department of Otolaryngology—Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAChristina M Sloan-Heggen - Medical Scientist Training Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADiana Kolbe - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAThomas Casavant - Center for Bioinformatics and Computational Biology, Departments of Electrical and Computer Engineering and Biomedical Engineering, University of Iowa College of Engineering, Iowa City, IA 52242, USAMichael J Schnieders - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USACarla Nishimura - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USATerry Braun - Center for Bioinformatics and Computational Biology, Departments of Electrical and Computer Engineering and Biomedical Engineering, University of Iowa College of Engineering, Iowa City, IA 52242, USARichard J.H Smith - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.103(4), pp.484-497
- DOI
- 10.1016/j.ajhg.2018.08.006
- PMID
- 30245029
- PMCID
- PMC6174355
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000055, name: NIDCD, award: RO1s DC003544, DC002842, DC012049
- Language
- English
- Date published
- 10/04/2018
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; Otolaryngology; Internal Medicine; Iowa Institute of Human Genetics
- Record Identifier
- 9984006493902771
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