Journal article
Assessing variants of uncertain significance implicated in hearing loss using a comprehensive deafness proteome
Human genetics, Vol.142(6), pp.819-834
06/01/2023
DOI: 10.1007/s00439-023-02559-9
PMCID: PMC10182131
PMID: 37086329
Abstract
Hearing loss is the leading sensory deficit, affecting ~ 5% of the population. It exhibits remarkable heterogeneity across 223 genes with 6328 pathogenic missense variants, making deafness-specific expertise a prerequisite for ascribing phenotypic consequences to genetic variants. Deafness-implicated variants are curated in the Deafness Variation Database (DVD) after classification by a genetic hearing loss expert panel and thorough informatics pipeline. However, seventy percent of the 128,167 missense variants in the DVD are "variants of uncertain significance" (VUS) due to insufficient evidence for classification. Here, we use the deep learning protein prediction algorithm, AlphaFold2, to curate structures for all DVD genes. We refine these structures with global optimization and the AMOEBA force field and use DDGun3D to predict folding free energy differences (∆∆G
) for all DVD missense variants. We find that 5772 VUSs have a large, destabilizing ∆∆G
that is consistent with pathogenic variants. When also filtered for CADD scores (> 25.7), we determine 3456 VUSs are likely pathogenic at a probability of 99.0%. Of the 224 genes in the DVD, 166 genes (74%) exhibit one or more missense variants predicted to cause a pathogenic change in protein folding stability. The VUSs prioritized here affect 119 patients (~ 3% of cases) sequenced by the OtoSCOPE targeted panel. Approximately half of these patients previously received an inconclusive report, and reclassification of these VUSs as pathogenic provides a new genetic diagnosis for six patients.
Details
- Title: Subtitle
- Assessing variants of uncertain significance implicated in hearing loss using a comprehensive deafness proteome
- Creators
- Mallory R Tollefson - University of IowaRose A Gogal - University of IowaA Monique Weaver - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa Hospitals and Clinics, Iowa City, IA, 52242, USAAmanda M Schaefer - University of IowaRobert J Marini - University of IowaHela Azaiez - University of IowaDiana L Kolbe - University of IowaDonghong Wang - University of IowaAmy E Weaver - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa Hospitals and Clinics, Iowa City, IA, 52242, USAThomas L Casavant - University of IowaTerry A Braun - University of IowaRichard J H Smith - University of Iowa Hospitals and ClinicsMichael J Schnieders - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Human genetics, Vol.142(6), pp.819-834
- DOI
- 10.1007/s00439-023-02559-9
- PMID
- 37086329
- PMCID
- PMC10182131
- NLM abbreviation
- Hum Genet
- ISSN
- 0340-6717
- eISSN
- 1432-1203
- Grant note
- T32GM008365 / NIGMS NIH HHS R01DC017955 / NIDCD NIH HHS R01DC002842 / NIDCD NIH HHS R01 DC017955 / NIDCD NIH HHS R01DC012049 / NIDCD NIH HHS
- Language
- English
- Date published
- 06/01/2023
- 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; Chemical and Biochemical Engineering; Otolaryngology; Internal Medicine; Iowa Institute of Human Genetics
- Record Identifier
- 9984585427402771
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