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PreprintCited by 20Genomics and Rare DiseasesHearing, Cochlea, Tinnitus, GeneticsProtein Structure and Dynamics

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Assessing Variants of Uncertain Significance Implicated in Hearing Loss Using a Comprehensive Deafness Proteome

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Tollefson, Mallory R., Gogal, Rose A., Weaver, A. Monique, Schaefer, Amanda M., Marini, Robert J., Azaiez, Hela, Kolbe, Diana L., Wang, Donghong, Weaver, Amy E., Casavant, Thomas L., Braun, Terry A., Smith, Richard J. H., Schnieders, Michael·2023·Human Genetics
DOI 10.21203/rs.3.rs-2508462/v1PMC PMC10182131

Preprint — published as 10.1007/s00439-023-02559-9 · Paper page

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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.

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Metadata

Authors
Tollefson, M. R., Gogal, R. A., Weaver, A. M., Schaefer, A. M., Marini, R. J., Azaiez, H., Kolbe, D. L., Wang, D., Weaver, A. E., Casavant, T. L., Braun, T. A., Smith, R. J. H., & Schnieders, M.
Affiliations
  • University of Iowa (US)
  • University of Iowa Hospitals and Clinics (US)
  • The University of Iowa
Corresponding author
  • Smith, Richard J. H.
  • Schnieders, Michael
ORCID
Venue
Human Genetics
Publisher
Springer Science and Business Media LLC
Published
2023-02-01
Volume
142
Issue
6
Pages
819-834
ISSN
0018-7348 (ISSN-L)
DOI
10.21203/rs.3.rs-2508462/v1
PMC
PMC10182131
OpenAlex
W4366742193
Cited by
20
References
1
Citations by year
2026: 3 · 2025: 7 · 2024: 10
FWCI
3.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Human Genetics (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • National Science Foundation (000390183, 1751688)
  • American Association of University Women
  • National Institutes of Health (NIH T32)
  • Center for Biocatalysis and Bioprocessing, University of Iowa (2 T32 GM008365)
  • National Institute on Deafness and Other Communication Disorders (R01DC017955, R01DC002842, R01DC012049)
  • National Institute of General Medical Sciences (T32GM008365)
  • Division of Chemistry (1751688, CHE-1751688)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
variants of uncertain significance, hereditary hearing loss, missense mutations, protein folding stability, folding free energy, AlphaFold2, AMOEBA force field, CADD score, variant reclassification, genetic diagnosis

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