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

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

Hum Genet. 2016 Dec;135(12):1355-1364. doi: 10.1007/s00439-016-1727-x. Epub 2016 Sep 15.

Authors

Affiliations

¹ 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.
² Wadsworth Center, New York State Department of Health, 120 New Scotland Avenue, Albany, NY, 12201-2002, USA.
³ California Birth Defects Monitoring Program, California Department of Public Health, 1615 Capitol Avenue, MS 8304, Sacramento, CA, 95899-7420, USA.
⁴ Department of Epidemiology, College of Public Health, The University of Iowa, 145 N. Riverside Drive, S416 CPHB, Iowa City, IA, 52242, USA.
⁵ Congenital Malformations Registry, New York State Department of Health, Empire State Plaza-Corning Tower, Albany, NY, 12237, USA.
⁶ University at Albany School of Public Health, 1400 Washington Avenue, Albany, NY, 12222, USA.
⁷ Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Building 50, 50 South Drive, MSC 8004, Bethesda, MD, 20892, USA.
⁸ Department of Pediatrics, Stanford University School of Medicine, Medical Office Building, 1265 Welch Road Room X159, Stanford, CA, 94305, USA.
⁹ Department of Epidemiology and Biostatistics, University of California San Francisco School of Medicine, 550 16th Street, San Francisco, CA, 94158, USA.
¹⁰ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Body Patterning / genetics
DNA Copy Number Variations / genetics*
Female
Fibroblast Growth Factors / genetics*
Genotype
Heart Defects, Congenital / genetics*
Heart Defects, Congenital / pathology
Heterotaxy Syndrome / genetics*
Heterotaxy Syndrome / pathology
Humans
Infant
Male
MicroRNAs
Polymorphism, Single Nucleotide
RNA Splicing Factors / genetics*
Signal Transduction

Substances

FGF12 protein, human
MicroRNAs
RBFOX1 protein, human
RNA Splicing Factors
Fibroblast Growth Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding