Harper, A.R. orcid.org/0000-0001-5327-0328, Bowman, M., Hayesmoore, J.B.G. et al. (60 more authors) (2020) Reevaluation of the South Asian MYBPC3Δ25bp Intronic Deletion in Hypertrophic Cardiomyopathy. Circulation: Genomic and Precision Medicine, 13 (3). ARTN e002783. pp. 101-109. ISSN 2574-8300
Abstract
Background:
The common intronic deletion, MYBPC3Δ25, detected in 4% to 8% of South Asian populations, is reported to be associated with cardiomyopathy, with ≈7-fold increased risk of disease in variant carriers. Here, we examine the contribution of MYBPC3Δ25 to hypertrophic cardiomyopathy (HCM) in a large patient cohort.
Methods:
Sequence data from 2 HCM cohorts (n=5393) was analyzed to determine MYBPC3Δ25 frequency and co-occurrence of pathogenic variants in HCM genes. Case-control and haplotype analyses were performed to compare variant frequencies and assess disease association. Analyses were also undertaken to investigate the pathogenicity of a candidate variant MYBPC3 c.1224-52G>A.
Results:
Our data suggest that the risk of HCM, previously attributed to MYBPC3Δ25, can be explained by enrichment of a derived haplotype, MYBPC3Δ25/−52, whereby a small subset of individuals bear both MYBPC3Δ25 and a rare pathogenic variant, MYBPC3 c.1224-52G>A. The intronic MYBPC3 c.1224-52G>A variant, which is not routinely evaluated by gene panel or exome sequencing, was detected in ≈1% of our HCM cohort.
Conclusions:
The MYBPC3 c.1224-52G>A variant explains the disease risk previously associated with MYBPC3Δ25 in the South Asian population and is one of the most frequent pathogenic variants in HCM in all populations; genotyping services should ensure coverage of this deep intronic mutation. Individuals carrying MYBPC3Δ25 alone are not at increased risk of HCM, and this variant should not be tested in isolation; this is important for the large majority of the 100 million individuals of South Asian ancestry who carry MYBPC3Δ25 and would previously have been declared at increased risk of HCM.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 The Authors. Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. |
Keywords: | exome; genotype; haplotypes; humans; introns |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Biomedical Imaging Science Dept (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 13 Feb 2024 16:08 |
Last Modified: | 13 Feb 2024 16:08 |
Published Version: | https://www.ahajournals.org/doi/10.1161/CIRCGEN.11... |
Status: | Published |
Publisher: | American Heart Association |
Identification Number: | 10.1161/circgen.119.002783 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:209119 |