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In Genetics in medicine : official journal of the American College of Medical Genetics

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 ( ), highlighting broad opportunities for improved pathogenicity prediction through disease specificity.

Zhang Xiaolei, Walsh Roddy, Whiffin Nicola, Buchan Rachel, Midwinter William, Wilk Alicja, Govind Risha, Li Nicholas, Ahmad Mian, Mazzarotto Francesco, Roberts Angharad, Theotokis Pantazis I, Mazaika Erica, Allouba Mona, de Marvao Antonio, Pua Chee Jian, Day Sharlene M, Ashley Euan, Colan Steven D, Michels Michelle, Pereira Alexandre C, Jacoby Daniel, Ho Carolyn Y, Olivotto Iacopo, Gunnarsson Gunnar T, Jefferies John L, Semsarian Chris, Ingles Jodie, O’Regan Declan P, Aguib Yasmine, Yacoub Magdi H, Cook Stuart A, Barton Paul J R, Bottolo Leonardo, Ware James S


Brugada syndrome, cardiomyopathy, long QT syndrome, missense variant interpretation, pathogenicity prediction