Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects.
Genomic disorders and rare copy number abnormalities are identified in 15-25% of patients with syndromic conditions, but their prevalence in individuals with isolated birth defects is less clear. A spectrum of congenital heart defects (CHDs) is seen in heterotaxy, a highly heritable and genetically heterogeneous multiple congenital anomaly syndrome resulting from failure to properly establish left-right (L-R) organ asymmetry during early embryonic development. To identify novel genetic causes of heterotaxy, we analysed copy number variants (CNVs) in 225 patients with heterotaxy and heterotaxy-spectrum CHDs using array-based genotyping methods. Clinically relevant CNVs were identified in approximately 20% of patients and encompassed both known and putative heterotaxy genes. Patients were carefully phenotyped, revealing a significant association of abdominal situs inversus with pathogenic or likely pathogenic CNVs, while d-transposition of the great arteries was more frequently associated with common CNVs. Identified cytogenetic abnormalities ranged from large unbalanced translocations to smaller, kilobase-scale CNVs, including a rare, single exon deletion in ZIC3, a gene known to cause X-linked heterotaxy. Morpholino loss-of-function experiments in Xenopus support a role for one of these novel candidates, the platelet isoform of phosphofructokinase-1 (PFKP) in heterotaxy. Collectively, our results confirm a high CNV yield for array-based testing in patients with heterotaxy, and support use of CNV analysis for identification of novel biological processes relevant to human laterality.This article is part of the themed issue 'Provocative questions in left-right asymmetry'.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.|Department of Pediatrics and Medical and Molecular Genetics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Jason R
JR
Cowan
Department of Pediatrics and Medical and Molecular Genetics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|Department of Clinical Biochemistry, University of Tabuk, Tabuk 71491, Kingdom of Saudi Arabia.
Muhammad
M
Tariq
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Chad
C
Shaw
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Mitchell
M
Rao
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
John W
JW
Belmont
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Seema R
SR
Lalani
Cincinnati Children's Hospital Medical Center, Division of Human Genetics, Cincinnati, OH 45229, USA.
Teresa A
TA
Smolarek
Department of Pediatrics and Medical and Molecular Genetics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA stware@iu.edu.
Stephanie M
SM
Ware
D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D005838:Genotype; D059446:Heterotaxy Syndrome / Q000235:genetics*; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010732:Phosphofructokinase-1 / Q000235:genetics* / Q000378:metabolism
D010732:Phosphofructokinase-1
congenital heart defects; copy number variation; heterotaxy; left–right patterning; phosphofructokinase