Rare genetic mutations in Pakistani patients with dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a leading cause of heart failure, and heart transplantation globally. There is enlargement of left ventricle of the heart impairing the systolic function in this disorder. The involvement of genetic factors in the pathogenesis of DCM has been reported in up to 50% of the cases. However, due to the complexity and heterogeneity of the disease, the complete pathophysiology remains unclear. In this study, whole exomes of five unrelated patients of idiopathic DCM were sequenced to an average depth of 100× using Illumina HiSeq4000 system. The analysis of the data with in silico tools SIFT, Polyphen2, and CADD showed 494 rare (AF < 1.0%) missense SNVs predicted as deleterious. Detrimental variants in genes highly expressed in cardiac tissue included 3 rare allele frequency loss-of-function SNVs in C2orf40, MYOM3, and TMED4 genes, a homozygous frameshift insertion in RTKN2, and a splice site homozygous deletion in SLC6A6 in at least one of the patients. The stop-gained SNV rs143187236 of MYOM3 (myomesin 3) was found in perfect linkage disequilibrium (r = 1.0) with its neighboring missense SNV rs149105212 in two of the patients, representing the role of myomesin 3 in pathophysiology of DCM. Allele frequency comparison showed three variants rs375563861 (C2orf40), rs143187236 (MYOM3), and rs564181443 (RTKN2) having 3 fold or higher allele frequency in South Asians than in the global populations. The identified pathogenic variants can be used in risk assessment and precision therapy in DCM patients.