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J. Cardiovasc. Dev. Dis. 2017, 4(3), 11;

Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy

Mayo Graduate School of Biomedical Sciences, Molecular Pharmacology and Experimental Therapeutics Track, Mayo Clinic, Rochester, MN 55905, USA
Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA
Author to whom correspondence should be addressed.
Received: 30 June 2017 / Revised: 2 August 2017 / Accepted: 4 August 2017 / Published: 8 August 2017
(This article belongs to the Special Issue Genetics and Treatment of Dilated Cardiomyopathy)
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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. View Full-Text
Keywords: dilated cardiomyopathy; heart failure; pediatric; genetics; whole exome sequencing; mutation dilated cardiomyopathy; heart failure; pediatric; genetics; whole exome sequencing; mutation

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Long, P.A.; Evans, J.M.; Olson, T.M. Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy. J. Cardiovasc. Dev. Dis. 2017, 4, 11.

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