Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases: The case of hypertrophic cardiomyopathy

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Title: Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases: The case of hypertrophic cardiomyopathy
Authors: Walsh, R
Mazzarotto, F
Whiffin, N
Buchan, R
Midwinter, W
Wilk, A
Li, N
Felkin, L
Ingold, N
Govind, R
Ahmad, M
Mazaika, E
Allouba, M
Zhang, X
De Marvao, A
Day, SM
Ashley, E
Colan, SD
Michels, M
Pereira, AC
Jacoby, D
Ho, CY
Thomson, KL
Watkins, H
Barton, PJR
Olivotto, I
Cook, SA
Ware, JS
Item Type: Journal Article
Abstract: Background International guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as (likely) pathogenic, prioritising control of false-positive rate over test sensitivity and diagnostic yield. Genetic testing is also more likely informative in individuals with well-characterised variants from extensively studied European-ancestry populations. Inherited cardiomyopathies are relatively common Mendelian diseases that allow empirical calibration and assessment of this framework. Methods We compared rare variants in large hypertrophic cardiomyopathy (HCM) cohorts (up to 6179 cases) to reference populations to identify variant classes with high prior likelihoods of pathogenicity, as defined by etiological fraction (EF). We analysed the distribution of variants using a bespoke unsupervised clustering algorithm to identify gene regions in which variants are significantly clustered in cases. Results Analysis of variant distribution identified regions in which variants are significantly enriched in cases and variant location was a better discriminator of pathogenicity than generic computational functional prediction algorithms. Non-truncating variant classes with an EF ≥ 0.95 were identified in five established HCM genes. Applying this approach leads to an estimated 14–20% increase in cases with actionable HCM variants, i.e. variants classified as pathogenic/likely pathogenic that might be used for predictive testing in probands’ relatives. Conclusions When found in a patient confirmed to have disease, novel variants in some genes and regions are empirically shown to have a sufficiently high probability of pathogenicity to support a “likely pathogenic” classification, even without additional segregation or functional data. This could increase the yield of high confidence actionable variants, consistent with the framework and recommendations of current guidelines. The techniques outlined offer a consistent and unbiased approach to variant interpretation for Mendelian disease genetic testing. We propose adaptations to ACMG/AMP guidelines to incorporate such evidence in a quantitative and transparent manner.
Issue Date: 29-Jan-2019
Date of Acceptance: 21-Dec-2018
URI: http://hdl.handle.net/10044/1/66905
DOI: https://dx.doi.org/10.1186/s13073-019-0616-z
ISSN: 1756-994X
Publisher: BMC
Journal / Book Title: Genome Medicine
Volume: 11
Copyright Statement: © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Sponsor/Funder: British Heart Foundation
Fondation Leducq
Fondation Leducq
Wellcome Trust
Department of Health
Wellcome Trust
Royal Brompton & Harefield NHS Foundation Trust
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: SP/10/10/28431
11 CVD-01
11 CVD-01
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
Variant interpretation
Mendelian genetics
Hypertrophic cardiomyopathy
AMP guidelines
ACMG/AMP guidelines
Hypertrophic cardiomyopathy
Mendelian genetics
Variant interpretation
0604 Genetics
1103 Clinical Sciences
Publication Status: Published
Open Access location: https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-019-0616-z
Article Number: ARTN 5
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine

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