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Philos Trans R Soc Lond B Biol Sci
2016 Dec 19;3711710:. doi: 10.1098/rstb.2015.0406.
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Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects.
Cowan JR
,
Tariq M
,
Shaw C
,
Rao M
,
Belmont JW
,
Lalani SR
,
Smolarek TA
,
Ware SM
.
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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'.
Adams,
Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates.
2006, Pubmed,
Xenbase
Adams,
Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates.
2006,
Pubmed
,
Xenbase
Altmann,
The latent-TGFbeta-binding-protein-1 (LTBP-1) is expressed in the organizer and regulates nodal and activin signaling.
2002,
Pubmed
,
Xenbase
Bartz,
Early and late results of the modified fontan operation for heterotaxy syndrome 30 years of experience in 142 patients.
2006,
Pubmed
Beyenbach,
The V-type H+ ATPase: molecular structure and function, physiological roles and regulation.
2006,
Pubmed
Blum,
Xenopus, an ideal model system to study vertebrate left-right asymmetry.
2009,
Pubmed
,
Xenbase
Blum,
Symmetry breakage in the vertebrate embryo: when does it happen and how does it work?
2014,
Pubmed
,
Xenbase
Boone,
Detection of clinically relevant exonic copy-number changes by array CGH.
2010,
Pubmed
Brancati,
CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders.
2007,
Pubmed
Branford,
Regulation of gut and heart left-right asymmetry by context-dependent interactions between xenopus lefty and BMP4 signaling.
2000,
Pubmed
,
Xenbase
Cast,
An essential and highly conserved role for Zic3 in left-right patterning, gastrulation and convergent extension morphogenesis.
2012,
Pubmed
,
Xenbase
Cooper,
A copy number variation morbidity map of developmental delay.
2011,
Pubmed
Coppieters,
CEP290, a gene with many faces: mutation overview and presentation of CEP290base.
2010,
Pubmed
Cowan,
Genetic and functional analyses of ZIC3 variants in congenital heart disease.
2014,
Pubmed
Craige,
CEP290 tethers flagellar transition zone microtubules to the membrane and regulates flagellar protein content.
2010,
Pubmed
Davidson,
Alterations in phosphofructokinase isoenzymes during early human development. Establishment of adult organ-specific patterns.
1983,
Pubmed
Davis,
TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum.
2011,
Pubmed
Dworkin,
Carbon metabolism in early amphibian embryos.
1991,
Pubmed
,
Xenbase
Essner,
Kupffer's vesicle is a ciliated organ of asymmetry in the zebrafish embryo that initiates left-right development of the brain, heart and gut.
2005,
Pubmed
Fakhro,
Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning.
2011,
Pubmed
,
Xenbase
Gegg,
Flattop regulates basal body docking and positioning in mono- and multiciliated cells.
2014,
Pubmed
Girirajan,
Human copy number variation and complex genetic disease.
2011,
Pubmed
Goetz,
The spinocerebellar ataxia-associated gene Tau tubulin kinase 2 controls the initiation of ciliogenesis.
2012,
Pubmed
Gokey,
The V-ATPase accessory protein Atp6ap1b mediates dorsal forerunner cell proliferation and left-right asymmetry in zebrafish.
2015,
Pubmed
Haffner,
Nicalin and its binding partner Nomo are novel Nodal signaling antagonists.
2004,
Pubmed
Heasman,
Beta-catenin signaling activity dissected in the early Xenopus embryo: a novel antisense approach.
2000,
Pubmed
,
Xenbase
Kahn,
Phosphofructokinase in human fetus.
1980,
Pubmed
Kennedy,
Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia.
2007,
Pubmed
Khurana,
Integrative annotation of variants from 1092 humans: application to cancer genomics.
2013,
Pubmed
Kim,
Outcome of 200 patients after an extracardiac Fontan procedure.
2008,
Pubmed
Kosaki,
Left-right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB.
1999,
Pubmed
,
Xenbase
Lange,
Fltp(T2AiCre): a new knock-in mouse line for conditional gene targeting in distinct mono- and multiciliated tissues.
2012,
Pubmed
Lin,
Heterotaxy: associated conditions and hospital-based prevalence in newborns.
2000,
Pubmed
Lin,
Laterality defects in the national birth defects prevention study (1998-2007): birth prevalence and descriptive epidemiology.
2014,
Pubmed
Lisowski,
Congenital heart disease in pregnancies complicated by maternal diabetes mellitus. An international clinical collaboration, literature review, and meta-analysis.
2010,
Pubmed
Maurano,
Systematic localization of common disease-associated variation in regulatory DNA.
2012,
Pubmed
Mohapatra,
Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations.
2009,
Pubmed
Nonaka,
Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein.
1998,
Pubmed
Øyen,
Recurrence of congenital heart defects in families.
2009,
Pubmed
Pegoraro,
Pfkfb (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) isoforms display a tissue-specific and dynamic expression during Xenopus laevis development.
2013,
Pubmed
,
Xenbase
Pegoraro,
PFKFB4 controls embryonic patterning via Akt signalling independently of glycolysis.
2015,
Pubmed
,
Xenbase
Poultney,
Identification of small exonic CNV from whole-exome sequence data and application to autism spectrum disorder.
2013,
Pubmed
Raddatz,
Changes in activity of the regulatory glycolytic enzymes and of the pyruvate-dehydrogenase complex during the development of Xenopus laevis.
1986,
Pubmed
,
Xenbase
Rigler,
Novel copy-number variants in a population-based investigation of classic heterotaxy.
2015,
Pubmed
Ristow,
Deficiency of phosphofructo-1-kinase/muscle subtype in humans impairs insulin secretion and causes insulin resistance.
1997,
Pubmed
Roessler,
Reduced NODAL signaling strength via mutation of several pathway members including FOXH1 is linked to human heart defects and holoprosencephaly.
2008,
Pubmed
Rudd,
Segmental duplications mediate novel, clinically relevant chromosome rearrangements.
2009,
Pubmed
Russell,
Functional analysis of candidate genes in 2q13 deletion syndrome implicates FBLN7 and TMEM87B deficiency in congenital heart defects and FBLN7 in craniofacial malformations.
2014,
Pubmed
Schweickert,
The nodal inhibitor Coco is a critical target of leftward flow in Xenopus.
2010,
Pubmed
,
Xenbase
Schweickert,
Cilia-driven leftward flow determines laterality in Xenopus.
2007,
Pubmed
,
Xenbase
Shapiro,
Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy.
2014,
Pubmed
Soemedi,
Contribution of global rare copy-number variants to the risk of sporadic congenital heart disease.
2012,
Pubmed
Song,
ACVR1, a therapeutic target of fibrodysplasia ossificans progressiva, is negatively regulated by miR-148a.
2012,
Pubmed
Stowe,
The centriolar satellite proteins Cep72 and Cep290 interact and are required for recruitment of BBS proteins to the cilium.
2012,
Pubmed
Su,
The a-subunit of the V-type H+-ATPase interacts with phosphofructokinase-1 in humans.
2003,
Pubmed
Su,
Human H+ATPase a4 subunit mutations causing renal tubular acidosis reveal a role for interaction with phosphofructokinase-1.
2008,
Pubmed
Sulik,
Morphogenesis of the murine node and notochordal plate.
1994,
Pubmed
Sutherland,
Disorders of left-right asymmetry: heterotaxy and situs inversus.
2009,
Pubmed
Sutherland,
Zic3 is required in the migrating primitive streak for node morphogenesis and left-right patterning.
2013,
Pubmed
Swisher,
Increased postoperative and respiratory complications in patients with congenital heart disease associated with heterotaxy.
2011,
Pubmed
Todorovic,
Long form of latent TGF-beta binding protein 1 (Ltbp1L) is essential for cardiac outflow tract septation and remodeling.
2007,
Pubmed
Tran,
THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia.
2008,
Pubmed
Vandenberg,
Far from solved: a perspective on what we know about early mechanisms of left-right asymmetry.
2010,
Pubmed
Vick,
Flow on the right side of the gastrocoel roof plate is dispensable for symmetry breakage in the frog Xenopus laevis.
2009,
Pubmed
,
Xenbase
Ward,
Evidence of abundant purifying selection in humans for recently acquired regulatory functions.
2012,
Pubmed
Ware,
Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects.
2004,
Pubmed
,
Xenbase
Yu,
A recurrent 1.71 Mb genomic imbalance at 2q13 increases the risk of developmental delay and dysmorphism.
2012,
Pubmed
Zarrei,
A copy number variation map of the human genome.
2015,
Pubmed
Zhang,
Copy number variation in human health, disease, and evolution.
2009,
Pubmed
Zhang,
MicroRNA-148a promotes myogenic differentiation by targeting the ROCK1 gene.
2012,
Pubmed
Zhu,
Genetics of human heterotaxias.
2006,
Pubmed
