Reevaluation of the South Asian MYBPC3(Δ25bp) Intronic Deletion in Hypertrophic Cardiomyopathy

The common intronic deletion, MYBPC3(Δ25), 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 MYBPC3(Δ25) to hypertrophic cardiomyopathy (HCM) in a large patient cohort. METHODS: Sequence data from 2 HCM cohorts (n=5393) was analyzed to determine MYBPC3(Δ25) 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 MYBPC3(Δ25), can be explained by enrichment of a derived haplotype, MYBPC3(Δ25/)(−52), whereby a small subset of individuals bear both MYBPC3(Δ25) 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 MYBPC3(Δ25) 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 MYBPC3(Δ25) 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 MYBPC3(Δ25) and would previously have been declared at increased risk of HCM.