A Re-evaluation of the South Asian MYBPC3 Δ25 Intronic Deletion in Hypertrophic Cardiomyopathy.

Background: The common intronic deletion,MYBPC3(Delta 25), detected in 4% to 8% of South Asian populations, is reported to be associated with cardiomyopathy, with approximate to 7-fold increased risk of disease in variant carriers. Here, we examine the contribution ofMYBPC3(Delta 25)to hypertrophic cardiomyopathy (HCM) in a large patient cohort. Methods: Sequence data from 2 HCM cohorts (n=5393) was analyzed to determineMYBPC3(Delta 25)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 variantMYBPC3c.1224-52G>A. Results: Our data suggest that the risk of HCM, previously attributed toMYBPC3(Delta 25), can be explained by enrichment of a derived haplotype,MYBPC3(Delta 25/-52), whereby a small subset of individuals bear bothMYBPC3(Delta 25)and a rare pathogenic variant,MYBPC3c.1224-52G>A. The intronicMYBPC3c.1224-52G>A variant, which is not routinely evaluated by gene panel or exome sequencing, was detected in approximate to 1% of our HCM cohort. Conclusions: TheMYBPC3c.1224-52G>A variant explains the disease risk previously associated withMYBPC3(Delta 25)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 carryingMYBPC3(Delta 25)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 carryMYBPC3(Delta 25)and would previously have been declared at increased risk of HCM.