Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions
Theotokis, Pantazis I.
de Marvao, Antonio
Pua, Chee Jian
Day, Sharlene M.
Colan, Steven D.
Pereira, Alexandre C.
Ho, Carolyn Y.
Gunnarsson, Gunnar T.
Jefferies, John L.
O’Regan, Declan P.
Yacoub, Magdi H.
Cook, Stuart A.
Barton, Paul J. R.
Genetics in Medicine
Nature Publishing Group US
MetadataShow full item record
Zhang, X., Walsh, R., Whiffin, N., Buchan, R., Midwinter, W., Wilk, A., Govind, R., et al. (2020). Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions. Genetics in Medicine, 23 (1), 69-79. https://doi.org/10.1038/s41436-020-00972-3
Funder: Science and Technology Development Fund; doi: https://doi.org/10.13039/
Funder: Al-Alfi Foundation
Funder: Magdi Yacoub Heart Foundation
Funder: Rosetrees and Stoneygate Imperial College Research Fellowship
Funder: National Health and Medical Research Council (Australia)
Abstract: Purpose: Accurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning variant prioritization tools are imprecise and ignore important parameters defining gene–disease relationships, e.g., distinct consequences of gain-of-function versus loss-of-function variants. We hypothesized that incorporating disease-specific information would improve tool performance. Methods: We developed a disease-specific variant classifier, CardioBoost, that estimates the probability of pathogenicity for rare missense variants in inherited cardiomyopathies and arrhythmias. We assessed CardioBoost’s ability to discriminate known pathogenic from benign variants, prioritize disease-associated variants, and stratify patient outcomes. Results: CardioBoost has high global discrimination accuracy (precision recall area under the curve [AUC] 0.91 for cardiomyopathies; 0.96 for arrhythmias), outperforming existing tools (4–24% improvement). CardioBoost obtains excellent accuracy (cardiomyopathies 90.2%; arrhythmias 91.9%) for variants classified with >90% confidence, and increases the proportion of variants classified with high confidence more than twofold compared with existing tools. Variants classified as disease-causing are associated with both disease status and clinical severity, including a 21% increased risk (95% confidence interval [CI] 11–29%) of severe adverse outcomes by age 60 in patients with hypertrophic cardiomyopathy. Conclusions: A disease-specific variant classifier outperforms state-of-the-art genome-wide tools for rare missense variants in inherited cardiac conditions (https://www.cardiodb.org/cardioboost/), highlighting broad opportunities for improved pathogenicity prediction through disease specificity.
Article, article, pathogenicity prediction, missense variant interpretation, cardiomyopathy, long QT syndrome, Brugada syndrome
Alan Turing Institute (EP/N510129/1)
External DOI: https://doi.org/10.1038/s41436-020-00972-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/329350