A Common Variant in the
            <i>PTPN11</i>
            Gene Contributes to the Risk of Tetralogy of Fallot

Goodship, Judith A.; Hall, Darroch; Töpf, Ana; Mamasoula, Chrysovalanto; Griffin, Helen; Rahman, Thahira; Glen, Elise; Tan, Huay Lin; Doza, Julián Palomino; Relton, Caroline L; Bentham, Jamie; Bhattacharya, Shoumo; Cosgrove, Catherine; Brook, David; Granados-Riveron, Javier T; Bu’Lock, Frances; O’Sullivan, John; Stuart, Graham; Parsons, Jonathan; Cordell, Heather J.; Keavney, Bernard

doi:10.1161/circgenetics.111.962035

Cited by 35 publications

(29 citation statements)

References 35 publications

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“…Our rationale for this study design was that if such loci had been detectable, their population impact would have been much larger than any locus influencing only one phenotypic subgroup. The region of chromosome 12 that we have previously shown to be associated with the risk of the CHD condition Tetralogy of Fallot (TOF) 14 was not significantly associated with CHD risk, either overall or in any subgroup, in the present study (which did not include patients with TOF). Similarly, the association between SNPs at 4p16 and ASD was not apparent for CHD conditions other than ASD.…”

contrasting

confidence: 63%

Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16

et al. 2013

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We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls, and included patients from each of the three major clinical CHD categories (septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no regions achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P=9.5×10−7) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N=340 cases), and this was replicated in a further 417 ASD cases and 2520 controls (replication P=5.0×10−5; OR in replication cohort 1.40 [95% CI 1.19-1.65]; combined P=2.6×10−10). Genotype accounted for ~9% of the population attributable risk of ASD.

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confidence: 63%

Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16

et al. 2013

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“…S7). This exact 12q24.13 duplication has not been reported in the non-syndromic CHD literature, but variants in PTPN11 have been associated with non-syndromic TOF (Cordell et al 2013; Goodship et al 2012). Furthermore, PTPN11 mutations are known to cause a spectrum of cardiac developmental defects, and are observed frequently in patients with Noonan syndrome and LEOPARD syndrome (Lauriol et al 2015; Sznajer et al 2007).…”

Section: Resultsmentioning

confidence: 81%

Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome

et al. 2016

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The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS; MIM #192430; 188400) is the most common microdeletion syndrome. The phenotypic presentation of 22q11DS is highly variable; approximately 60–75 % of 22q11DS patients have been reported to have a congenital heart defect (CHD), mostly of the conotruncal type, and/or aortic arch defect. The etiology of the cardiac phenotypic variability is not currently known for the majority of patients. We hypothesized that rare copy number variants (CNVs) outside the 22q11.2 deleted region may modify the risk of being born with a CHD in this sensitized population. Rare CNV analysis was performed using Affymetrix SNP Array 6.0 data from 946 22q11DS subjects with CHDs (n = 607) or with normal cardiac anatomy (n = 339). Although there was no significant difference in the overall burden of rare CNVs, an overabundance of CNVs affecting cardiac-related genes was detected in 22q11DS individuals with CHDs. When the rare CNVs were examined with regard to gene interactions, specific cardiac networks, such as Wnt signaling, appear to be overrepresented in 22q11DS CHD cases but not 22q11DS controls with a normal heart. Collectively, these data suggest that CNVs outside the 22q11.2 region may contain genes that modify risk for CHDs in some 22q11DS patients.

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“…Some genes are responsible for TOF, including mutations in NKX2.5,[15222627] GATA4 interacts physically with NKX2.5,[28] GATA6,[293031] JAG1,[11323334] JAG5,[35] TBX20,[36] BVES,[37] mitochondrial ATP8 gene,[38] epigenetic changes of some genes such as NKX2.5,[39] HAND1,[39] VANGL2,[40] and single nucleotide polymorphisms of some genes such as PTPN11[41] and MTHFR. [42] In addition, TOF has been observed to be concomitant with some syndromes and associations such as Down, Alagille, DiGeorge, and CHARGE syndromes, and VACTERL association.…”

Section: Discussionmentioning

confidence: 99%

Existence of mutations in the homeodomain-encoding region of NKX2.5 gene in Iranian patients with tetralogy of Fallot

Kheirollahi

Khosravi

Ashouri³

et al. 2016

J Res Med Sci

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Background:Tetralogy of Fallot (TOF), the most common cyanotic heart defect and one of the most common congenital heart diseases, occurs mostly sporadically and nonsyndromically. The underlying molecular genetic mechanism is not known. Therefore, the existence of mutations in the homeodomain-encoding region of NKX2.5 gene in Iranian patients with tetralogy of Fallot is evaluated.Materials and Methods:In the present study, we analyzed the peripheral blood samples of27 patients in order to find any mutation in the 180 bp homeodomain-encoding region of NKX2.5 gene, which is known to be involved in heart development and diseases. DNA was extracted and all the samples were amplified by polymerase chain reaction (PCR) and sequenced.Results:Twenty-seven patients were included in the study. Twenty-five of them were infants and children (6 days to 11 years of age), one was a teenager (14-years of age), and another was a 33-year-old man [mean ± standard deviation (SD): 5.80 ± 3.90 years]. Thirteen patents were males (mean ± SD: 6.587077 ± 5.02 years) and 14 were females (mean ± SD: 5.0726 ± 2.81 years). One synonymous variant, i.e., c.543G>A was identified in one patient.Conclusion:Mutations in the homeodomain-encoding region of NKX2.5 gene may not have an outstanding role in etiology of tetralogy of Fallot patients in Iran.

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A Common Variant in the PTPN11 Gene Contributes to the Risk of Tetralogy of Fallot

Cited by 35 publications

References 35 publications

Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16

Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16

Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome

Existence of mutations in the homeodomain-encoding region of NKX2.5 gene in Iranian patients with tetralogy of Fallot

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