Produção Nacional
Revisado por pares
Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions
2020; Elsevier BV; Volume: 23; Issue: 1 Linguagem: Inglês
10.1038/s41436-020-00972-3
ISSN1530-0366
AutoresXiaolei Zhang, Roddy Walsh, Nicola Whiffin, Rachel Buchan, William Midwinter, Alicja Wilk, Risha Govind, Nicholas Li, Mian Ahmad, Francesco Mazzarotto, Angharad M. Roberts, Pantazis Theotokis, Erica Mazaika, Mona Allouba, Antonio de Marvao, Chee Jian Pua, Sharlene M. Day, Euan A. Ashley, Steven D. Colan, Michelle Michels, Alexandre C. Pereira, Daniel Jacoby, Carolyn Y. Ho, Iacopo Olivotto, Gunnar Gunnarsson, John L. Jefferies, Chris Semsarian, Jodie Ingles, Declan P. O’Regan, Yasmine Aguib, Magdi H. Yacoub, Stuart A. Cook, Paul J.R. Barton, Leonardo Bottolo, James S. Ware,
Tópico(s)Genetic Neurodegenerative Diseases
ResumoPurposeAccurate 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.MethodsWe 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.ResultsCardioBoost 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.ConclusionsA 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.
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