Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions.

Autor:	Zhang X; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS, Foundation Trust London, London, United Kingdom., Walsh R; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS, Foundation Trust London, London, United Kingdom., Whiffin N; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS, Foundation Trust London, London, United Kingdom., Buchan R; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS, Foundation Trust London, London, United Kingdom., Midwinter W; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS, Foundation Trust London, London, United Kingdom., Wilk A; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS, Foundation Trust London, London, United Kingdom., Govind R; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS, Foundation Trust London, London, United Kingdom., Li N; Cardiovascular Research Centre, Royal Brompton and Harefield NHS, Foundation Trust London, London, United Kingdom.; MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom., Ahmad M; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS, Foundation Trust London, London, United Kingdom., Mazzarotto F; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.; Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy., Roberts A; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS, Foundation Trust London, London, United Kingdom., Theotokis PI; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS, Foundation Trust London, London, United Kingdom., Mazaika E; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS, Foundation Trust London, London, United Kingdom., Allouba M; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Aswan Heart Centre, Magdi Yacoub Heart Foundation, Aswan, Egypt., de Marvao A; MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom., Pua CJ; National Heart Centre, Singapore, Singapore., Day SM; Division of Cardiovascular Medicine and Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA., Ashley E; Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford, CA, USA., Colan SD; Department of Cardiology, Boston Children's Hospital, Boston, MA, USA., Michels M; Department of Cardiology, Thoraxcenter, Erasmus MC Rotterdam, Rotterdam, Netherlands., Pereira AC; Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil., Jacoby D; Department of Internal Medicine, Yale University, New Haven, CT, USA., Ho CY; Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA., Olivotto I; Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy., Gunnarsson GT; Faculty of Medicine, University of Iceland, Akureyri, Iceland., Jefferies JL; The Cardiovascular Institute, University of Tennessee, Memphis, TN, USA., Semsarian C; Centenary Institute, The University of Sydney, Sydney, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia., Ingles J; Centenary Institute, The University of Sydney, Sydney, Australia., O'Regan DP; MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom., Aguib Y; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Aswan Heart Centre, Magdi Yacoub Heart Foundation, Aswan, Egypt., Yacoub MH; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Aswan Heart Centre, Magdi Yacoub Heart Foundation, Aswan, Egypt., Cook SA; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS, Foundation Trust London, London, United Kingdom.; National Heart Centre, Singapore, Singapore.; Duke-National University of Singapore, Singapore, Singapore., Barton PJR; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS, Foundation Trust London, London, United Kingdom., Bottolo L; Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom. lb664@cam.ac.uk.; Alan Turing Institute, London, United Kingdom. lb664@cam.ac.uk.; MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom. lb664@cam.ac.uk., Ware JS; National Heart and Lung Institute, Imperial College London, London, United Kingdom. j.ware@imperial.ac.uk.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS, Foundation Trust London, London, United Kingdom. j.ware@imperial.ac.uk.; MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom. j.ware@imperial.ac.uk.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2021 Jan; Vol. 23 (1), pp. 69-79. Date of Electronic Publication: 2020 Oct 13.
DOI:	10.1038/s41436-020-00972-3
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Full text from SpringerLink