The prevalence of protein misfolding as a mechanism for hereditary deafness
5 affiliations
- 1Roy J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa, United States of America
- 2Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States of America
- 3Department of Otolaryngology, University of Iowa, Iowa City, Iowa, United States of America
- 4Department of Biochemistry and Molecular Biology, University of Iowa, Iowa City, Iowa, United States of America
- 5Department of Electrical and Computer Engineering, University of Iowa, Iowa City, Iowa, United States of America
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. Author summary: We investigate the impacts of single amino acid changes on protein structure and folding in the context of hearing loss. Hearing loss is the most common impairment of the main senses affecting nearly 5% of the world’s population. About 45% of people with hearing loss receive a diagnosis after targeted genetic testing. Here, we integrate biophysical data that quantifies the effect of a change to protein sequence on protein folding in combination with genetic data to improve our ability to identify protein amino acid changes that are likely to impact hearing. Our work leads to 12 patients receiving an upgraded diagnosis with their variant disrupting protein stability. Although the method is applied to hearing loss, it can be used for interpreting protein sequence changes in other disease contexts.
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BibTeX
@article{gogal2026prevalence,
title = {{The prevalence of protein misfolding as a mechanism for hereditary deafness}},
author = {Rose A. Gogal and Genevieve M. Cox and Diana L. Kolbe and Amanda M. Odell and Chloe E. Ovel and Katherine I. McCormick and Brian Hong and Hela Azaiez and Thomas L. Casavant and Richard J. H. Smith and Terry A. Braun and Michael J. Schnieders},
journal = {PLOS Genetics},
year = {2026},
month = sep,
doi = {10.1371/journal.pgen.1012085},
url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012085},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The prevalence of protein misfolding as a mechanism for hereditary deafness
AU - Rose A. Gogal
AU - Genevieve M. Cox
AU - Diana L. Kolbe
AU - Amanda M. Odell
AU - Chloe E. Ovel
AU - Katherine I. McCormick
AU - Brian Hong
AU - Hela Azaiez
AU - Thomas L. Casavant
AU - Richard J. H. Smith
AU - Terry A. Braun
AU - Michael J. Schnieders
PY - 2026
DA - 2026/09/30
JO - PLOS Genetics
DO - 10.1371/journal.pgen.1012085
UR - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012085
AB - 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. Author summary: We investigate the impacts of single amino acid changes on protein structure and folding in the context of hearing loss. Hearing loss is the most common impairment of the main senses affecting nearly 5% of the world’s population. About 45% of people with hearing loss receive a diagnosis after targeted genetic testing. Here, we integrate biophysical data that quantifies the effect of a change to protein sequence on protein folding in combination with genetic data to improve our ability to identify protein amino acid changes that are likely to impact hearing. Our work leads to 12 patients receiving an upgraded diagnosis with their variant disrupting protein stability. Although the method is applied to hearing loss, it can be used for interpreting protein sequence changes in other disease contexts.
SN - 1553-7404
ER -