Reevaluation of the South Asian MYBPC3Δ25bp Intronic Deletion in Hypertrophic Cardiomyopathy
| Autor: | Andrew R. Harper, Michael Bowman, Jesse B.G. Hayesmoore, Helen Sage, Silvia Salatino, Edward Blair, Carolyn Campbell, Bethany Currie, Anuj Goel, Karen McGuire, Elizabeth Ormondroyd, Kate Sergeant, Adam Waring, Jessica Woodley, Christopher M. Kramer, Stefan Neubauer, Martin Farrall, Hugh Watkins, Kate L. Thomson, Theodore Abraham, Lisa Anderson, Evan Appelbaum, Camillo Autore, Colin Berry, Elena Biagini, William Bradlow, Chiara Bucciarelli-Ducci, Amedeo Chiribiri, Lubna Choudhury, Andrew Crean, Dana Dawson, Milind Y. Desai, Eleanor Elstein, Andrew Flett, Matthias Friedrich, Stephen Heitner, Adam Helms, Carolyn Ho, Daniel L. Jacoby, Han Kim, Bette Kim, Eric Larose, Masliza Mahmod, Heiko Mahrholdt, Martin Maron, Gerry McCann, Michelle Michaels, Saidi Mohiddin, Sherif Nagueh, David Newby, Iacopo Olivotto, Anjali Owens, F. Pierre-Mongeon, Sanjay Prasad, Ornella Rimoldi, Michael Salerno, Jeanette Schulz-Menger, Mark Sherrid, Peter Swoboda, Albert van Rossum, Jonathan Weinsaft, James White, Eric Williamson |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male 0301 basic medicine haplotypes Asia South asia genotype introns Cardiomyopathy Disease 030204 cardiovascular system & hematology Biology Article 03 medical and health sciences 0302 clinical medicine Asian People Risk Factors Genotype medicine Humans Exome Aged Sequence Deletion Genetics Heart Failure Base Sequence Haplotype Hypertrophic cardiomyopathy General Medicine Original Articles Middle Aged Cardiomyopathy Hypertrophic medicine.disease 030104 developmental biology Increased risk Case-Control Studies ComputingMethodologies_DOCUMENTANDTEXTPROCESSING Female Carrier Proteins Cardiomyopathies exome |
| Zdroj: | Circulation. Genomic and Precision Medicine Circ Genom Precis Med |
| ISSN: | 2574-8300 |
| Popis: | Supplemental Digital Content is available in the text. 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. |
| Databáze: | OpenAIRE |
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