CardioClassifier: disease- and gene-specific computational decision support for clinical genome interpretation.
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Embargo End Date
ICR Authors
Authors
Whiffin, N
Walsh, R
Govind, R
Edwards, M
Ahmad, M
Zhang, X
Tayal, U
Buchan, R
Midwinter, W
Wilk, AE
Najgebauer, H
Francis, C
Wilkinson, S
Monk, T
Brett, L
O'Regan, DP
Prasad, SK
Morris-Rosendahl, DJ
Barton, PJR
Edwards, E
Ware, JS
Cook, SA
Walsh, R
Govind, R
Edwards, M
Ahmad, M
Zhang, X
Tayal, U
Buchan, R
Midwinter, W
Wilk, AE
Najgebauer, H
Francis, C
Wilkinson, S
Monk, T
Brett, L
O'Regan, DP
Prasad, SK
Morris-Rosendahl, DJ
Barton, PJR
Edwards, E
Ware, JS
Cook, SA
Document Type
Journal Article
Date
2018-10-01
Date Accepted
2017-12-05
Abstract
PURPOSE: Internationally adopted variant interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) are generic and require disease-specific refinement. Here we developed CardioClassifier ( http://www.cardioclassifier.org ), a semiautomated decision-support tool for inherited cardiac conditions (ICCs). METHODS: CardioClassifier integrates data retrieved from multiple sources with user-input case-specific information, through an interactive interface, to support variant interpretation. Combining disease- and gene-specific knowledge with variant observations in large cohorts of cases and controls, we refined 14 computational ACMG criteria and created three ICC-specific rules. RESULTS: We benchmarked CardioClassifier on 57 expertly curated variants and show full retrieval of all computational data, concordantly activating 87.3% of rules. A generic annotation tool identified fewer than half as many clinically actionable variants (64/219 vs. 156/219, Fisher's P = 1.1 × 10-18), with important false positives, illustrating the critical importance of disease and gene-specific annotations. CardioClassifier identified putatively disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with leading ICC laboratories. Through addition of manually curated data, variants found in over 40% of cardiomyopathy cases are fully annotated, without requiring additional user-input data. CONCLUSION: CardioClassifier is an ICC-specific decision-support tool that integrates expertly curated computational annotations with case-specific data to generate fast, reproducible, and interactive variant pathogenicity reports, according to best practice guidelines.
Citation
Genetics in medicine : official journal of the American College of Medical Genetics, 2018, 20 (10), pp. 1246 - 1254
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
1098-3600
eISSN
1530-0366
Collections
Research Team
Molecular & Population Genetics