Abstract
Dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. DCM typically remains clinically silent until adulthood, yet symptomatic disease can develop in childhood. We sought to identify the genetic basis of pediatric DCM in 15 sporadic and three affected-siblings cases, comprised of 21 affected children (mean age, five years) whose parents had normal echocardiograms (mean age, 39 years). Twelve underwent cardiac transplantation and five died with severe heart failure. Parent-offspring whole exome sequencing (WES) data were filtered for rare, deleterious, de novo and recessive variants. In prior work, we reported de novo mutations in TNNT2 and RRAGC and compound heterozygous mutations in ALMS1 and TAF1A among four cases in our cohort. Here, de novo mutations in established DCM genes—RBM20, LMNA, TNNT2, and PRDM16—were identified among five additional cases. The RBM20 mutation was previously reported in familial DCM. An identical unreported LMNA mutation was identified in two unrelated cases, both harboring gene-specific defects in cardiomyocyte nuclear morphology. Collectively, WES had a 50% diagnostic yield in our cohort, providing an explanation for pediatric heart failure and enabling informed family planning. Research is ongoing to discover novel DCM genes among the remaining families.
Highlights
Idiopathic dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder characterized by progressive degeneration of cardiac muscle that leads to heart failure
Clinical DCM gene panel testing had been independently performed in five cases and was non-diagnostic in four due to absence of the disease gene on the selected panel (ALMS1 in DC-86, PRDM16 in DC-97) or novelty of the disease gene (TAF1A in DC-82, RRAGC in DC-94)
An in-depth analysis of whole exome sequencing (WES) data for rare coding and splice-site variants within known DCM genes identified pathogenic de novo mutations in five pediatric cases
Summary
Idiopathic dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder characterized by progressive degeneration of cardiac muscle that leads to heart failure. A subset of patients develops symptomatic heart failure at a young age, suggesting unique pathogenic mechanisms for DCM within the pediatric age group. In both children and adults, end-stage DCM remains the most common indication for cardiac transplantation [2,3]. While mutations identified in more than 50 DCM genes have advanced understanding of disease pathobiology [4,5], the diagnostic yield of clinical gene panel testing for DCM is only 37% [6]. Beyond traditional candidate gene and locus mapping strategies for DCM gene discovery, whole exome sequencing (WES) in parent-offspring trios provides an efficient means to discover the genetic basis of sporadic DCM, and enhance the yield of molecular diagnostics. Together with our previously reported findings [7,8,9,10], we discovered causal mutations among functionally diverse genes in 50% of pediatric DCM cases
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