title: Copy-number variant analysis of classic heterotaxy highlights the importance of body patterning pathways.
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.
authors.affiliation: 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.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Hagen
authors.affiliation: Wadsworth Center, New York State Department of Health, 120 New Scotland Avenue, Albany, NY, 12201-2002, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sicko
authors.affiliation: Wadsworth Center, New York State Department of Health, 120 New Scotland Avenue, Albany, NY, 12201-2002, USA.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Kay
authors.affiliation: 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.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Rigler
authors.affiliation: 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.
authors.forename: Aggeliki
authors.initials: A
authors.lastname: Dimopoulos
authors.affiliation: California Birth Defects Monitoring Program, California Department of Public Health, 1615 Capitol Avenue, MS 8304, Sacramento, CA, 95899-7420, USA.
authors.forename: Shabbir
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: California Birth Defects Monitoring Program, California Department of Public Health, 1615 Capitol Avenue, MS 8304, Sacramento, CA, 95899-7420, USA.
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Doleman
authors.affiliation: 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.
authors.forename: Ruzong
authors.initials: R
authors.lastname: Fan
authors.affiliation: Department of Epidemiology, College of Public Health, The University of Iowa, 145 N. Riverside Drive, S416 CPHB, Iowa City, IA, 52242, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Romitti
authors.affiliation: Congenital Malformations Registry, New York State Department of Health, Empire State Plaza-Corning Tower, Albany, NY, 12237, USA.|University at Albany School of Public Health, 1400 Washington Avenue, Albany, NY, 12222, USA.
authors.forename: Marilyn L
authors.initials: ML
authors.lastname: Browne
authors.affiliation: Wadsworth Center, New York State Department of Health, 120 New Scotland Avenue, Albany, NY, 12201-2002, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Caggana
authors.affiliation: Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Building 50, 50 South Drive, MSC 8004, Bethesda, MD, 20892, USA.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Medical Office Building, 1265 Welch Road Room X159, Stanford, CA, 94305, USA.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Shaw
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco School of Medicine, 550 16th Street, San Francisco, CA, 94158, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Jelliffe-Pawlowski
authors.affiliation: 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.
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
mesh_terms: D019521:Body Patterning / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics*; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D059446:Heterotaxy Syndrome / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D035683:MicroRNAs; D020641:Polymorphism, Single Nucleotide; D000072260:RNA Splicing Factors / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C486356:FGF12 protein, human; D035683:MicroRNAs; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D005346:Fibroblast Growth Factors