Rare copy number variants in a population-based investigation of hypoplastic right heart syndrome

Aggeliki Dimopoulos; Robert J Sicko; Denise M Kay; Shannon L Rigler; Charlotte M Druschel; Michele Caggana; Marilyn L Browne; Ruzong Fan; Paul A Romitti; Lawrence C Brody; James L Mills

doi:10.1002/bdra.23586

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Rare copy number variants in a population-based investigation of hypoplastic right heart syndrome

Journal article

Peer reviewed

Rare copy number variants in a population-based investigation of hypoplastic right heart syndrome

Aggeliki Dimopoulos, Robert J Sicko, Denise M Kay, Shannon L Rigler, Charlotte M Druschel, Michele Caggana, Marilyn L Browne, Ruzong Fan, Paul A Romitti, Lawrence C Brody, …

Birth defects research, Vol.109(1), pp.8-15

01/20/2017

DOI: 10.1002/bdra.23586

PMCID: PMC5388571

PMID: 28009100

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Abstract

Hypoplastic right heart syndrome (HRHS) is a rare congenital defect characterized by underdevelopment of the right heart structures commonly accompanied by an atrial septal defect. Familial HRHS reports suggest genetic factor involvement. We examined the role of copy number variants (CNVs) in HRHS. We genotyped 32 HRHS cases identified from all New York State live births (1998-2005) using Illumina HumanOmni2.5 microarrays. CNVs were called with PennCNV and prioritized if they were ≥20 Kb, contained ≥10 SNPs and had minimal overlap with CNVs from in-house controls, the Database of Genomic Variants, HapMap3, and Childrens Hospital of Philadelphia database. We identified 28 CNVs in 17 cases; several encompassed genes important for right heart development. One case had a 2p16-2p23 duplication spanning LBH, a limb and heart development transcription factor. Lbh mis-expression results in right ventricular hypoplasia and pulmonary valve defects. This duplication also encompassed SOS1, a factor associated with pulmonary valve stenosis in Noonan syndrome. Sos1 mice display thin and poorly trabeculated ventricles. In another case, we identified a 1.5 Mb deletion associated with Williams-Beuren syndrome, a disorder that includes valvular malformations. A third case had a 24 Kb deletion upstream of the TGFβ ligand ITGB8. Embryos genetically null for Itgb8, and its intracellular interactant Band 4.1B, display lethal cardiac phenotypes. To our knowledge, this is the first study of CNVs in HRHS. We identified several rare CNVs that overlap genes related to right ventricular wall and valve development, suggesting that genetics plays a role in HRHS and providing clues for further investigation. Birth Defects Research 109:16-26, 2017. © 2016 Wiley Periodicals, Inc.

Phenotype

New York

Williams Syndrome - genetics

Heart Defects, Congenital - etiology

Oligonucleotide Array Sequence Analysis - methods

Humans

Child, Preschool

Genotype

Infant

Male

DNA Copy Number Variations - genetics

Comparative Genomic Hybridization - methods

Heart Defects, Congenital - genetics

Heart Ventricles - abnormalities

Polymorphism, Single Nucleotide - genetics

Female

Heart Defects, Congenital - metabolism

Heart Ventricles - metabolism

Integrin beta Chains - genetics

Child

Databases, Nucleic Acid

Philadelphia

Sequence Deletion - genetics

Details

Title: Subtitle: Rare copy number variants in a population-based investigation of hypoplastic right heart syndrome
Creators: Aggeliki Dimopoulos - Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
Robert J Sicko - Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York
Denise M Kay - Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York
Shannon L Rigler - Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
Charlotte M Druschel - Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York
Michele Caggana - Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York
Marilyn L Browne - Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York
Ruzong Fan - Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
Paul A Romitti - Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa
Lawrence C Brody - Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
James L Mills - Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
Resource Type: Journal article
Publication Details: Birth defects research, Vol.109(1), pp.8-15
DOI: 10.1002/bdra.23586
PMID: 28009100
PMCID: PMC5388571
NLM abbreviation: Birth Defects Res
ISSN: 2472-1727
eISSN: 2472-1727
Publisher: Wiley; United States
Grant note: Z01 HD008792-01 / Intramural NIH HHS HHSN275201100001I / NICHD NIH HHS HHSN275201100001C / NICHD NIH HHS HHSN275201100001G / NICHD NIH HHS U01 DD001035 / NCBDD CDC HHS N01DK73431 / NICHD NIH HHS
Language: English
Date published: 01/20/2017
Academic Unit: Epidemiology; Biostatistics
Record Identifier: 9983995009902771

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