Journal article
The prevalence of protein misfolding as a mechanism for hereditary deafness
PLoS genetics, Vol.22(9), e1012085
09/30/2026
DOI: 10.1371/journal.pgen.1012085
PMID: 42814786
Abstract
Hearing loss is the most common sensory deficit impacting ~5% of the world's population. The Deafness Variation Database (DVD) is a public resource of deafness variants, containing 381,924 missense variants across 224 genes, with 303,577 classified as a variant of uncertain significance (VUS). To address the challenge of evaluating each deafness associated VUS, we evaluate a family of probabilistic frameworks to quantify the strength of computational evidence based on ACMG/AMP recommendations. First, CADD and REVEL are compared using Bayesian models parameterized using either a ClinVar 2019 dataset or labeled DVD variants. The REVEL model built using the DVD dataset demonstrates the best accuracy, sensitivity, and specificity. Incorporation of (in)tolerance to missense variation based on sorting each gene into three bins (tolerant, average, intolerant) shows that intolerant DVD genes are consistent with a higher prior probability of being pathogenic (25.7%) than average (10.7%) or tolerant (8.7%) genes. Finally, the impact of protein folding stability was incorporated into the Bayesian model and surpassed the simpler versions while also offering a biophysical rationale for the disease mechanism. The 28,866 VUSs that reach a posterior probability of pathogenicity above 98% based on the protein-folding informed Bayesian model were prioritized as likely to be pathogenic. Overall, 54,752 missense variants (14.3% of 381,924) are predicted to cause modest protein folding destabilization of greater than 1.0 kcal/mol, while 18,706 of these are prioritized VUSs (34% of 54,752). 22,237 missense variants (6.2% of 381,924) are predicted to cause more severe protein folding destabilization of at least 2 kcal/mol with 12,424 being prioritized VUSs (55.8% of 22,237). From these VUSs, we identify twelve probands where the patient's genetic diagnosis is upgraded to likely pathogenic/pathogenic. We highlight two variants that cause clear structural disruption, demonstrating the impact of biophysical characterization on variant evaluation.
Details
- Title: Subtitle
- The prevalence of protein misfolding as a mechanism for hereditary deafness
- Creators
- Rose A Gogal - University of IowaGenevieve M Cox - University of IowaDiana L Kolbe - University of IowaAmanda M Odell - Department of Otolaryngology, University of Iowa, Iowa City, Iowa, United States of AmericaChloe E Ovel - University of IowaKatherine I McCormick - University of IowaBrian Hong - University of IowaHela Azaiez - University of IowaThomas L Casavant - University of IowaRichard J H Smith - University of IowaTerry A Braun - University of IowaMichael J Schnieders - University of Iowa
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.22(9), e1012085
- DOI
- 10.1371/journal.pgen.1012085
- PMID
- 42814786
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7404
- eISSN
- 1553-7404
- Publisher
- PLoS
- Grant note
- Division of Chemistry: CHE-2504153 National Institute on Deafness and Other Communication Disorders: R01DC002842 Graduate College, University of Iowa: Iowa Recruitment Fellowship National Institute of General Medical Sciences: T32GM008365
Funding to support RAG's efforts was partially provided from the Iowa Biotech Training Program as funded by a T32 grant awarded by the National Institute of General Medical Sciences Predoctoral Institutional Research Training Grant (NIGMS T32 GM008365) and administered by the Center for Biocatalysis and Bioprocessing (CBB) at the University of Iowa. RAG was also supported by a Graduate College Iowa Recruitment Fellowship. Author MJS was supported in part by National Science Foundation award CHE-2504153 for $596,090 to develop protein structure optimization and thermodynamics methods, which were leveraged in this work. Research reported in this publication was also supported by the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health under award numbers R01DC002842 (RJHS), R01DC012049 (TB, TLC, MJS, RJHS), and R01DC017955 (RJHS). The total federal funding associated with these NIH awards was $8,775,722. This project was financed with 100% federal funds and 0% non-governmental funds. Each author received partial salary support from one or more NIH awards. MJS also received partial salary support from the NSF. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
- Language
- English
- Date published
- 09/30/2026
- Academic Unit
- Electrical and Computer Engineering; Iowa Technology Institute; Biochemistry and Molecular Biology; Chemical and Biochemical Engineering; Otolaryngology; Iowa Institute of Human Genetics; Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Center for Biocatalysis and Bioprocessing; Internal Medicine
- Record Identifier
- 9985240282402771
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