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Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy

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 sporad...

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Autores principales: Long, Pamela A., Evans, Jared M., Olson, Timothy M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715713/
https://www.ncbi.nlm.nih.gov/pubmed/29367541
http://dx.doi.org/10.3390/jcdd4030011
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author Long, Pamela A.
Evans, Jared M.
Olson, Timothy M.
author_facet Long, Pamela A.
Evans, Jared M.
Olson, Timothy M.
author_sort Long, Pamela A.
collection PubMed
description 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.
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spelling pubmed-57157132018-01-19 Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy Long, Pamela A. Evans, Jared M. Olson, Timothy M. J Cardiovasc Dev Dis Article 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. MDPI 2017-08-08 /pmc/articles/PMC5715713/ /pubmed/29367541 http://dx.doi.org/10.3390/jcdd4030011 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Long, Pamela A.
Evans, Jared M.
Olson, Timothy M.
Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy
title Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy
title_full Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy
title_fullStr Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy
title_full_unstemmed Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy
title_short Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy
title_sort diagnostic yield of whole exome sequencing in pediatric dilated cardiomyopathy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715713/
https://www.ncbi.nlm.nih.gov/pubmed/29367541
http://dx.doi.org/10.3390/jcdd4030011
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