Mutations in GATA4, NKX2.5, CRELD1, and BMP4 are infrequently found in patients with congenital cardiac septal defects

Posch, Maximilian; Perrot, Andreas; Schmitt, Katharina; Mittelhaus, Sebastian; Esenwein, Eva-Maria; Stiller, Brigitte; Geier, Christian; Dietz, Rainer; Geßner, Reinhard; Özcelik, C.; Berger, Felix

doi:10.1002/ajmg.a.32042

Cited by 87 publications

(58 citation statements)

References 12 publications

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“…Moreover, an increasing recognition of contributing environmental 10,11 and epigenetic 12,13 factors has revealed a previously unanticipated breadth to CHD etiology. Families with Mendelian inheritance have been useful for identifying monogenic causes, although mutations in identified genes have been infrequently detected in unrelated patient cohorts 44 . Autosomal dominant, autosomal recessive, and X-linked inheritance patterns have all been reported, often in the context of additional non-cardiac malformations or syndromic disease, and each pose unique recurrence risks for affected families (Table 4).…”

Section: Genetics and Recurrencementioning

confidence: 99%

Genetics and Genetic Testing in Congenital Heart Disease

Cowan

Ware

2015

Clinics in Perinatology

119

122

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Section: Genetics and Recurrencementioning

confidence: 99%

Genetics and Genetic Testing in Congenital Heart Disease

Cowan

Ware

2015

Clinics in Perinatology

119

122

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“…9 Numerous mutations in GATA4 have been recognized in a wide range of cases, including tetralogy of Fallot (TOF), pulmonary stenosis, atrial septal defects (ASDs), ventricular septal defects, atrioventricular septal defects and patent ductus arteriosus. 4,[10][11][12][13][14][15][16][17] GATA6 is another member of the GATA family with expression and functions that overlap with GATA4 during cardiovascular development. 7 Recent experiments in animals have revealed critical roles for GATA6 in the development of the myocardium and cardiac morphogenesis, highlighting the potential involvement of GATA6 mutations in the pathogenesis of human CHD.…”

Section: Introductionmentioning

confidence: 99%

A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

et al. 2010

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GATA6 is a member of the GATA family of transcription factors, and its expression and functions overlap with those of GATA4 during heart development. Mutations in GATA4 have been related to human congenital heart diseases (CHDs) in several studies, whereas mutations in GATA6 have only recently been reported in patients with persistent truncus arteriosus. Animal experiments have revealed critical roles for GATA6 in the development of the myocardium and cardiac morphogenesis, thereby highlighting the potential involvement of GATA6 defects in the pathogenesis of CHDs. Here, we screened the GATA6 in 270 individuals with sporadic CHDs by direct sequencing. After identification of the mutation, a luciferase reporter assay and real-time quantitative polymerase chain reaction were performed to detect functional changes in the mutant transcription factor. The same heterozygous missense mutation (Ser184Asn) was identified in three patients, including one with tetralogy of Fallot and two with atrial septal defects. This mutation was not found in 500 unrelated ethnically matched healthy subjects. Direct sequencing of this region in the parents of these three patients revealed the same mutation in one of the parents for each patient, and one of the parent carriers presented with a bicuspid aortic valve. Biological analysis revealed clearly decreased transcriptional activity of GATA6 Ser184Asn in vitro. All these data suggest that GATA6 Ser184Asn is a novel mutation associated with CHDs and has an important role in disease pathogenesis.

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“…The 4406 alleles of African American origin in the ESP dataset did also not show this mutation. Further, the disease genes GATA4 and NKX2.5 that are known to cause nonsyndromic ASD, were excluded as cause of the disease in this patient as described previously [4].…”

Section: Resultsmentioning

confidence: 99%

“…Various mutations in transcription factors and sarcomeric genes were described in different studies [3]. We have analyzed different genes involved in the pathogenesis of CHDs and could identify mutations in ASD patients [4,5,6].…”

Section: Introductionmentioning

confidence: 99%

CCN1 Mutation is Associated with Atrial Septal Defect

et al. 2014

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The genetic basis of congenital heart disease remains unknown in most of the cases. Recently, a novel mouse model shed new light on the role of CCN1/CYR61, a matricellular regulatory factor, in cardiac morphogenesis. In a candidate gene approach, we analyzed a cohort of 143 patients with atrial septal defects (ASD) by sequencing the coding exons of CCN1. In addition to three frequent polymorphisms, we identified an extremely rare novel heterozygous missense mutation (c.139C>T; p.R47W) in one patient with severe ASD. The mutation leads to an exchange of residues with quite different properties in a highly conserved position of the Nterminal insulin-like growth factor binding protein (IGFBP) module. Further bioinformatic analysis, exclusion of known ASD disease genes as well as the exclusion of the mutation in a very high number of ethnically matched controls (more than 1000 individuals) and in public genetic databases indicates that the p.R47W variant is a probable disease-associated mutation. The report about ASD in mice in heterozygous Ccn1 +/-animals strongly supports this notion. Our study is the first to suggest a relationship between a probable CCN1 mutation and ASD. Our purpose here was to draw attention to CCN1, a gene that we believe may be important for genetic analysis in patients with congenital heart disease.

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Mutations in GATA4, NKX2.5, CRELD1, and BMP4 are infrequently found in patients with congenital cardiac septal defects

Cited by 87 publications

References 12 publications

Genetics and Genetic Testing in Congenital Heart Disease

Genetics and Genetic Testing in Congenital Heart Disease

A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

CCN1 Mutation is Associated with Atrial Septal Defect

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