Preprint
Assessing Variants of Uncertain Significance Implicated in Hearing Loss Using a Comprehensive Deafness Proteome
Research Square
American Journal Experts
02/01/2023
DOI: 10.21203/rs.3.rs-2508462/v1
PMCID: PMC9915777
PMID: 36778238
Abstract
Hearing loss is the leading sensory deficit, affecting ~ 5% of the population. It exhibits remarkable heterogeneity across 223 genes with 6,328 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
Fold
) for all DVD missense variants. We find that 5,772 VUSs have a large, destabilizing ∆∆G
Fold
that is consistent with pathogenic variants. When also filtered for CADD scores (> 25.7), we determine 3,456 VUSs are likely pathogenic at a probability of 99.0%. These VUSs 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 - University of IowaAmanda 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 - University of IowaThomas L. Casavant - University of IowaTerry A. Braun - University of IowaRichard J. H. Smith - University of IowaMichael Schnieders - University of Iowa
- Resource Type
- Preprint
- Publication Details
- Research Square
- DOI
- 10.21203/rs.3.rs-2508462/v1
- PMID
- 36778238
- PMCID
- PMC9915777
- Publisher
- American Journal Experts
- Language
- English
- Date posted
- 02/01/2023
- 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
- 9984366049202771
Metrics
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