Key result
Whole exome sequencing identified a de novo missense mutation in TNNT2 and recessive compound heterozygous truncating mutations in XIRP2 in an 11-year-old female with sporadic dilated cardiomyopathy.
Case Report (n=1)
Whole exome sequencing identified XIRP2 as a novel modifier gene that, synergistically with a TNNT2 mutation, contributes to early-onset severe dilated cardiomyopathy.
Supports XIRP2 as candidate modifier in pediatric dilated cardiomyopathy; hypothesis-generating and requires validation before clinical adoption.
BACKGROUND: Idiopathic dilated cardiomyopathy (DCM) is typically diagnosed in adulthood, yet familial cases exhibit variable age-dependent 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.
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Long et al. (2015) conducted a case report in Sporadic Dilated Cardiomyopathy (n=1). Whole exome sequencing was evaluated on Discovery of the molecular basis of sporadic dilated cardiomyopathy. Whole exome sequencing identified a de novo missense mutation in TNNT2 and recessive compound heterozygous truncating mutations in XIRP2 in an 11-year-old female with sporadic dilated cardiomyopathy.
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