title: Genetic Variants in Isolated Ebstein Anomaly Implicated in Myocardial Development Pathways.
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.
authors: Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America.
authors: Robert J
authors: http://orcid.org/0000-0001-7521-9742
authors: RJ
authors: Sicko
authors: Congenital Malformations Registry, New York State Department of Health, Albany, New York, United States of America.|Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York, United States of America.
authors: Marilyn L
authors: http://orcid.org/0000-0002-1872-2787
authors: ML
authors: Browne
authors: 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.|Department of Neonatology, Walter Reed National Military Medical Center, Bethesda, Maryland, United States of America.
authors: Shannon L
authors: http://orcid.org/0000-0003-2984-8710
authors: SL
authors: Rigler
authors: Congenital Malformations Registry, New York State Department of Health, Albany, New York, United States of America.|Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York, United States of America.
authors: Charlotte M
authors: CM
authors: Druschel
authors: Congenital Malformations Registry, New York State Department of Health, Albany, New York, United States of America.
authors: Gang
authors: http://orcid.org/0000-0003-1928-2047
authors: G
authors: Liu
authors: 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.
authors: Ruzong
authors: R
authors: Fan
authors: Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa, United States of America.
authors: Paul A
authors: http://orcid.org/0000-0001-5393-9984
authors: PA
authors: Romitti
authors: Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America.
authors: Michele
authors: M
authors: Caggana
authors: Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America.
authors: Denise M
authors: http://orcid.org/0000-0002-9928-2698
authors: DM
authors: Kay
authors: 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 America.
authors: Lawrence C
authors: LC
authors: Brody
authors: 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.
authors: James L
authors: JL
authors: Mills
mesh_terms: D000328:Adult; D056915:DNA Copy Number Variations; D004437:Ebstein Anomaly / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D014644:Genetic Variation; D023281:Genomics; D005838:Genotype; D006321:Heart / Q000254:growth & development*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D055815:Young Adult