Copy-number variant analysis of classic heterotaxy highlights the importance of body patterning pathways

Erin M Hagen; Robert J Sicko; Denise M Kay; Shannon L Rigler; Aggeliki Dimopoulos; Shabbir Ahmad; Margaret H Doleman; Ruzong Fan; Paul A Romitti; Marilyn L Browne; Michele Caggana; Lawrence C Brody; Gary M Shaw; Laura L Jelliffe-Pawlowski; James L Mills

doi:10.1007/s00439-016-1727-x

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Copy-number variant analysis of classic heterotaxy highlights the importance of body patterning pathways

Journal article

Peer reviewed

Copy-number variant analysis of classic heterotaxy highlights the importance of body patterning pathways

Erin M Hagen, Robert J Sicko, Denise M Kay, Shannon L Rigler, Aggeliki Dimopoulos, Shabbir Ahmad, Margaret H Doleman, Ruzong Fan, Paul A Romitti, Marilyn L Browne, …

Human genetics, Vol.135(12), pp.1355-1364

12/2016

DOI: 10.1007/s00439-016-1727-x

PMCID: PMC5065782

PMID: 27637763

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Abstract

Classic heterotaxy consists of congenital heart defects with abnormally positioned thoracic and abdominal organs. We aimed to uncover novel, genomic copy-number variants (CNVs) in classic heterotaxy cases. A microarray containing 2.5 million single-nucleotide polymorphisms (SNPs) was used to genotype 69 infants (cases) with classic heterotaxy identified from California live births from 1998 to 2009. CNVs were identified using the PennCNV software. We identified 56 rare CNVs encompassing genes in the NODAL (NIPBL, TBX6), BMP (PPP4C), and WNT (FZD3) signaling pathways, not previously linked to classic heterotaxy. We also identified a CNV involving FGF12, a gene previously noted in a classic heterotaxy case. CNVs involving RBFOX1 and near MIR302F were detected in multiple cases. Our findings illustrate the importance of body patterning pathways for cardiac development and left/right axes determination. FGF12, RBFOX1, and MIR302F could be important in human heterotaxy, because they were noted in multiple cases. Further investigation into genes involved in the NODAL, BMP, and WNT body patterning pathways and into the dosage effects of FGF12, RBFOX1, and MIR302F is warranted.

Heterotaxy Syndrome - genetics

Signal Transduction

Humans

Heart Defects, Congenital - pathology

Fibroblast Growth Factors - genetics

Genotype

Infant

Male

DNA Copy Number Variations - genetics

RNA Splicing Factors - genetics

Heart Defects, Congenital - genetics

MicroRNAs

Female

Polymorphism, Single Nucleotide

Body Patterning - genetics

Heterotaxy Syndrome - pathology

Details

Title: Subtitle: Copy-number variant analysis of classic heterotaxy highlights the importance of body patterning pathways
Creators: Erin M Hagen - Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Boulevard, Bethesda, MD, 20892, USA
Robert J Sicko - Wadsworth Center, New York State Department of Health, 120 New Scotland Avenue, Albany, NY, 12201-2002, USA
Denise M Kay - Wadsworth Center, New York State Department of Health, 120 New Scotland Avenue, Albany, NY, 12201-2002, USA
Shannon L Rigler - Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Boulevard, Bethesda, MD, 20892, USA
Aggeliki Dimopoulos - Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Boulevard, Bethesda, MD, 20892, USA
Shabbir Ahmad - California Birth Defects Monitoring Program, California Department of Public Health, 1615 Capitol Avenue, MS 8304, Sacramento, CA, 95899-7420, USA
Margaret H Doleman - California Birth Defects Monitoring Program, California Department of Public Health, 1615 Capitol Avenue, MS 8304, Sacramento, CA, 95899-7420, USA
Ruzong Fan - Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Boulevard, Bethesda, MD, 20892, USA
Paul A Romitti - Department of Epidemiology, College of Public Health, The University of Iowa, 145 N. Riverside Drive, S416 CPHB, Iowa City, IA, 52242, USA
Marilyn L Browne - University at Albany School of Public Health, 1400 Washington Avenue, Albany, NY, 12222, USA
Michele Caggana - Wadsworth Center, New York State Department of Health, 120 New Scotland Avenue, Albany, NY, 12201-2002, USA
Lawrence C Brody - Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Building 50, 50 South Drive, MSC 8004, Bethesda, MD, 20892, USA
Gary M Shaw - Department of Pediatrics, Stanford University School of Medicine, Medical Office Building, 1265 Welch Road Room X159, Stanford, CA, 94305, USA
Laura L Jelliffe-Pawlowski - Department of Epidemiology and Biostatistics, University of California San Francisco School of Medicine, 550 16th Street, San Francisco, CA, 94158, USA
James L Mills - Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Boulevard, Bethesda, MD, 20892, USA. jamesmills@nih.gov
Resource Type: Journal article
Publication Details: Human genetics, Vol.135(12), pp.1355-1364
DOI: 10.1007/s00439-016-1727-x
PMID: 27637763
PMCID: PMC5065782
NLM abbreviation: Hum Genet
ISSN: 1432-1203
eISSN: 1432-1203
Publisher: Germany
Grant note: HHSN275201100001C / NICHD NIH HHS Z01 HD008792-01 / Intramural NIH HHS U01 DD001033 / NCBDD CDC HHS HHSN275201100001I / NICHD NIH HHS R01 HL092330 / NHLBI NIH HHS HHSN275201100001G / NICHD NIH HHS U01 DD001035 / NCBDD CDC HHS N01DK73431 / NICHD NIH HHS
Language: English
Date published: 12/2016
Academic Unit: Epidemiology; Biostatistics
Record Identifier: 9983996069002771

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