Reevaluation of the South Asian Intronic Deletion in Hypertrophic Cardiomyopathy.

BACKGROUND

The common intronic deletion, , 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 to hypertrophic cardiomyopathy (HCM) in a large patient cohort.

METHODS

Sequence data from 2 HCM cohorts (n=5393) was analyzed to determine 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 c.1224-52G>A.

RESULTS

Our data suggest that the risk of HCM, previously attributed to , can be explained by enrichment of a derived haplotype, , whereby a small subset of individuals bear both and a rare pathogenic variant, c.1224-52G>A. The intronic 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 c.1224-52G>A variant explains the disease risk previously associated with 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 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 and would previously have been declared at increased risk of HCM.