Journal article
Genetic Variants in Isolated Ebstein Anomaly Implicated in Myocardial Development Pathways
PloS one, Vol.11(10), pp.e0165174-e0165174
2016
DOI: 10.1371/journal.pone.0165174
PMCID: PMC5082909
PMID: 27788187
Abstract
Ebstein anomaly (EA) is a rare heart defect in which the tricuspid valve is malformed and displaced. The tricuspid valve abnormalities can lead to backflow of blood from the right ventricle to the right atrium, preventing proper circulation of blood to the lungs. Although the etiology of EA is largely unresolved, increased prevalence of EA in those with a family history of congenital heart disease suggests EA has a genetic component. Copy number variants (CNVs) are a major source of genetic variation and have been implicated in a range of congenital heart defect phenotypes. We performed a systematic, genome-wide search for CNVs in 47 isolated EA cases using genotyping microarrays. In addition, we used a custom HaloPlex panel to sequence three known EA genes and 47 candidate EA genes. We identified 35 candidate CNVs in 24 (51%) EA cases. Rare sequence variants in genes associated with cardiomyopathy were identified in 11 (23%) EA cases. Two CNVs near the transcriptional repressor HEY1, a member of the NOTCH signaling pathway, were identified in three unrelated cases. All other candidate CNVs were each identified in a single case. At least 11 of 35 candidate CNVs include genes involved in myocardial development or function, including multiple genes in the BMP signaling pathway. We identified enrichment of gene sets involved in histone modification and cardiomyocyte differentiation, supporting the involvement of the developing myocardium in the etiology of EA. Gene set enrichment analysis also identified ribosomal RNA processing, a potentially novel pathway of altered cardiac development in EA. Our results suggest an altered myocardial program may contribute to abnormal tricuspid valve development in EA. Future studies should investigate abnormal differentiation of cardiomyocytes as a potential etiological factor in EA.
Details
- Title: Subtitle
- Genetic Variants in Isolated Ebstein Anomaly Implicated in Myocardial Development Pathways
- Creators
- Robert J Sicko - Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of AmericaMarilyn L Browne - Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York, United States of AmericaShannon L Rigler - Department of Neonatology, Walter Reed National Military Medical Center, Bethesda, Maryland, United States of AmericaCharlotte M Druschel - Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York, United States of AmericaGang Liu - Congenital Malformations Registry, New York State Department of Health, Albany, New York, United States of AmericaRuzong Fan - Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of AmericaPaul A Romitti - Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa, United States of AmericaMichele Caggana - Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of AmericaDenise M Kay - Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of AmericaLawrence C Brody - Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of AmericaJames L Mills - Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.11(10), pp.e0165174-e0165174
- DOI
- 10.1371/journal.pone.0165174
- PMID
- 27788187
- PMCID
- PMC5082909
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- Public Library of Science; United States
- Grant note
- DOI: 10.13039/100009633, name: Eunice Kennedy Shriver National Institute of Child Health and Human Development, award: HHSN275201100001I-HHSN27500005; DOI: 10.13039/100009633, name: Eunice Kennedy Shriver National Institute of Child Health and Human Development, award: N01-DK-73431; DOI: 10.13039/100000051, name: National Human Genome Research Institute
- Language
- English
- Date published
- 2016
- Academic Unit
- Epidemiology; Biostatistics
- Record Identifier
- 9983996058602771
Metrics
40 Record Views