Exome sequencing identifies pathogenic and modifier mutations in a child with sporadic dilated cardiomyopathy

Background-Idiopathic dilated cardiomyopathy (DCM) is typically diagnosed in adulthood, yet familial cases exhibit variable agedependent penetrance and a subset of patients develop sporadic DCM in childhood. We sought to discover the molecular basis of sporadic DCM in an 11-year-old female with severe heart failure necessitating cardiac transplantation. Methods and Results-Parental echocardiograms excluded asymptomatic DCM. Whole exome sequencing was performed on the family trio and filtered for rare, deleterious, recessive, and de novo variants. Of the 8 candidate genes identified, only 2 had a role in cardiac physiology. A de novo missense mutation in TNNT2 was identified, previously reported and functionally validated in familial DCM with markedly variable penetrance. Additionally, recessive compound heterozygous truncating mutations were identified in XIRP2, a member of the ancient Xin gene family, which governs intercalated disc (ICD) maturation. Histomorphological analysis of explanted heart tissue revealed misregistration, mislocalization, and shortening of ICDs, findings similar to Xirp2^-/- mice. Conclusions-The synergistic effects of TNNT2 and XIRP2 mutations, resulting in perturbed sarcomeric force generation and transmission, respectively, would account for an early-onset heart failure phenotype. Whereas the importance of Xin proteins in cardiac development has been well established in animal models, this study implicates XIRP2 as a novel modifier gene in the pathogenesis of DCM.