Search of Somatic Mutations of NKX2-5 and GATA4 Genes in Chinese Patients with Sporadic Congenital Heart Disease

Yin, Jing; Qian, Jiang; Dai, Genyin; Wang, Chunli; Qin, Yong; Xu, Ting; Li, Zewei; Zhang, Han; Yang, Shiwei

doi:10.1007/s00246-018-1955-z

Cited by 12 publications

(6 citation statements)

References 27 publications

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“…Previous study found in the tissues of heart and blood, one recognized single‐nucleotide polymorphism (SNP) (rs2277923) in NKX2‐5 and one recognized SNP (rs56166237) in GATA4 . In contrast to our study, their study presented that NKX2‐5 and GATA4 mutations have no role in sporadic CHD pathogenesis (Yin et al, ).…”

Section: Discussioncontrasting

confidence: 99%

Association of NKX2‐5, GATA4, and TBX5 polymorphisms with congenital heart disease in Egyptian children

Behiry

Alazzouny

Sabry

et al. 2019

Molec Gen & Gen Med

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Background Several genes encoding transcription factors are known to be the primary cause of congenital heart disease. NKX2‐5 and GATA4 were the first congenital heart disease–causing genes identified by linkage analysis. This study designed to study the association of five single–nucleotide variants of NKX2‐5, GATA4 , and TBX5 genes with sporadic nonsyndromic cases of a congenital cardiac septal defect in Egyptian children. Methods Venous blood samples from 150 congenital heart disease children (including a ventricular septal defect, atrial septal defect, tetralogy of Fallot, and patent ductus arteriosus) and 90 apparently healthy of matched age and sex were studied by polymerase chain reaction followed by direct sequencing in order to study two single–nucleotide variants of NKX2‐5 (rs2277923, rs28936670), two single–nucleotide variants of GATA4 (rs368418329, rs56166237) and one single–nucleotide variant TBX5 ( rs6489957). The distribution of genotype and allele frequency in the congenital heart diseases (CHD) group and control group were analyzed. Results We found different genotype frequencies of the two variants of NKX2‐5 , as CT genotype of rs2277923 was present in 58% and 36% in cases and control respectively, and TT genotype present in 6% of the cases. Also regarding missense variant rs28936670, heterozygous AG presented in 82% of the cases. Also, we observed a five prime UTR variant rs368418329, GT (42% of the cases) and GG (46% of the cases) genotypes showed the most frequent presentation in cases. While regarding a synonymous variant rs56166237, GT and GG were the most presented in cases (41.4%, 56% respectively) in contrast to control group (20%, 1.7% respectively). Also, a synonymous variant in TBX5 , the distribution of genotype frequency was significantly different between the CHD group and control group. CT genotype of TBX5 ‐rs6489957 was found in 12 ASD, 24 VSD, six PDA, three aortic coarctation and nine fallot that represent 42% of the cases. Conclusions Significantly higher frequency of different allelle of five variants was observed in cases when compared to the control group, with significant risky effect for the development of septal defect. In addition to two polymorphisms of NKX2‐5 (rs2277923, rs28936670) variant in the cardiac septal defect, two variants in GATA4 (rs368418329, rs56166237) and one variant in TBX5 (rs6489957) seem to have a role in the pathogenesis of congenital heart disease.

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Section: Discussioncontrasting

confidence: 99%

Association of NKX2‐5, GATA4, and TBX5 polymorphisms with congenital heart disease in Egyptian children

Behiry

Alazzouny

Sabry

et al. 2019

Molec Gen & Gen Med

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“…Esposito et al ( 104 ) utilized freshly frozen cardiac tissue samples of right ventricular myocardium and matched blood samples from nine cases undergoing surgical treatment for TOF and 24 patients with left heart hypoplasia to evaluate the incidence of somatic GATA4 mutations in heart tissue by direct sequencing analysis; no somatic or germline mutations were identified. Yin et al ( 105 ) performed direct PCR-sequencing analysis of GATA4 on genomic DNA purified from heart tissue and peripheral blood cells of 98 cases with sporadic congenital heart disease and found two well-known SNPs (rs3729856 and rs56166237) in GATA4 in both heart tissue and blood samples, indicating a role of germline GATA4 variations in development of congenital heart disease. Given these conflicting reports on the contribution of somatic mutations to congenital heart disease, the finding of a somatic mutation of GATA4 in a case of TOF is rare and may depend on various factors such as analytical methods, ethnicity and environmental factors.…”

Section: Discussionmentioning

confidence: 99%

Somatic GATA4 mutation contributes to tetralogy of Fallot

Abhinav,

Li,

Huang

et al. 2024

Exp Ther Med

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Tetralogy of Fallot (TOF) is the most prevalent cyanotic congenital heart pathology and causes infant morbidity and mortality worldwide. GATA-binding protein 4 (GATA4) serves as a pivotal transcriptional factor for embryonic cardiogenesis and germline GATA4 mutations are causally linked to TOF. However, the effects of somatic GATA4 mutations on the pathogenesis of TOF remain to be ascertained. In the present study, sequencing assay of GATA4 was performed utilizing genomic DNA derived from resected heart tissue specimens as well as matched peripheral blood specimens of 62 patients with non-familial TOF who underwent surgical treatment for TOF. Sequencing of GATA4 was also performed using the heart tissue specimens as well as matched peripheral venous blood samples of 68 sporadic cases who underwent heart valve displacement because of rheumatic heart disorder and the peripheral venous whole blood samples of 216 healthy subjects. The function of the mutant was explored by dual-luciferase activity analysis. Consequently, a new GATA4 mutation, NM_002052.5:c.708T>G;p.(Tyr236*), was found in the heart tissue of one patient with TOF. No mutation was detected in the heart tissue of the 68 cases suffering from rheumatic heart disorder or in the venous blood samples of all 346 individuals. GATA4 mutant failed to transactivate its target gene, myosin heavy chain 6. Additionally, this mutation nullified the synergistic transactivation between GATA4 and T-box transcription factor 5 or NK2 homeobox 5, two genes causative for TOF. Somatic GATA4 mutation predisposes TOF, highlighting the significant contribution of somatic variations to the molecular pathogenesis underpinning TOF.

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“…In contrast to our association analysis, a previous study identified that the rs2277923 SNP on the NKX2-5 gene is linked to the sporadic ASDs in the Chinese Yunnan population and the A allele of rs2277923 is a potential risk factor resulting in ASDs [ 5 ]. Nevertheless, there are some different outcomes in CHD studies, which presented that rs2277923 has no role in sporadic CHD pathogenesis in Chinese patients [ 21 , 22 ]. The opposite research results may be related to the races and region differences.…”

Section: Discussionmentioning

confidence: 99%

Association of NFKB1, NKX2-5, GATA4 and RANKL gene polymorphisms with sporadic congenital heart disease in Greek patients

Aidinidou

Chatzikyriakidou

Giannopoulos

et al. 2021

Balkan Journal of Medical Genetics

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Congenital heart disease (CHD) is a group of structural defects of the heart and the great vessels, and one of the leading causes of death among infants and young adults. Several gene variants are involved in diverse mechanisms of cardiac and vessel development and could thus be considered candidate mutated genes for a congenital heart defect or a specific variant could predispose a person to CHD. In the present study, variants in four such genes are investigated for the first time in a group of young Greek CHD patients: the NFKB1 gene polymorphism (–94ins/ delATTG), rs28362491, NKX2-5 gene polymorphism rs2277923, GATA4 gene polymorphism rs11785481 and RANKL gene polymorphism rs4531631. A total of 43 CHD patients and 100 healthy adults were included in the study. The polymerase chain reaction-restriction fragment length polymorphism (PRC-RFLP) method was used to genotype the aforementioned polymorphisms of NFKB1, NKX2-5, GATA4 and RANKL. The association analysis identified that there was a protective association between CHD and the A allele of rs2277923 polymorphism (p = 0.004). The D allele of the rs28362491 polymorphism is also a likely risk factor for causing CHD (p = 0.006). The differences of the rs4531631 and rs11785481 variant contribution had no statistical significance between the groups (p >0.05). In conclusion, our results revealed that the rs28362491 and rs2277923 gene polymorphisms, but not the rs4531631 and rs11785481 polymorphisms, may contribute to CHD risk in a cohort of Greek CHD patients.

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Search of Somatic Mutations of NKX2-5 and GATA4 Genes in Chinese Patients with Sporadic Congenital Heart Disease

Cited by 12 publications

References 27 publications

Association of NKX2‐5, GATA4, and TBX5 polymorphisms with congenital heart disease in Egyptian children

Association of NKX2‐5, GATA4, and TBX5 polymorphisms with congenital heart disease in Egyptian children

Somatic GATA4 mutation contributes to tetralogy of Fallot

Association of NFKB1, NKX2-5, GATA4 and RANKL gene polymorphisms with sporadic congenital heart disease in Greek patients

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