| Autor: |
Tollefson MR; The University of Iowa., Gogal RA; The University of Iowa., Weaver AM; The University of Iowa., Schaefer AM; The University of Iowa., Marini RJ; The University of Iowa., Azaiez H; The University of Iowa., Kolbe DL; The University of Iowa., Wang D; The University of Iowa., Weaver AE; The University of Iowa., Casavant TL; The University of Iowa College of Nursing., Braun TA; The University of Iowa., Smith RJH; The University of Iowa., Schnieders M; The University of Iowa. |
| Jazyk: |
angličtina |
| Zdroj: |
Research square [Res Sq] 2023 Feb 01. Date of Electronic Publication: 2023 Feb 01. |
| DOI: |
10.21203/rs.3.rs-2508462/v1 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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