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

Kheirollahi, Majid; Khosravi, Fereshteh; Ashouri, Saeideh; Ahmadi, Alireza

doi:10.4103/1735-1995.179893

Cited by 7 publications

(4 citation statements)

References 38 publications

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“…It was found that there is only one polymorphism (A65G) in two atrial septal defect patients [ 22 ]. In another study, one synonymous variant (i.e., c. 543G > A) was identified in one patient from twenty-seven infants and children with tetralogy of Fallot [ 23 ]. According to our knowledge, the present study is the most comprehensive research on this gene in Iranian CHD patients.…”

Section: Discussionmentioning

confidence: 99%

Novel Point Mutations in the NKX2.5 Gene in Pediatric Patients with Non-Familial Congenital Heart Disease

et al. 2018

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Background and objective: Congenital heart disease (CHD) is the most common birth abnormality in the structure or function of the heart that affects approximately 1% of all newborns. Despite its prevalence and clinical importance, the etiology of CHD remains mainly unknown. Somatic and germline mutations in cardiac specific transcription factor genes have been identified as the factors responsible for various forms of CHD, particularly ventricular septal defects (VSDs), tetralogy of Fallot (TOF), and atrial septal defects (ASDs). p. NKX2.5 is a homeodomain protein that controls many of the physiological processes in cardiac development including specification and proliferation of cardiac precursors. The aim of our study was to evaluate the NKX2.5 gene mutations in sporadic pediatric patients with clinical diagnosis of congenital heart malformations. Materials and methods: In this study, we investigated mutations of the NKX2.5 gene’s coding region in 105 Iranian pediatric patients with non-familial CHD by polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP) and direct sequencing. Results: We observed a total of four mutations, of which, two were novel DNA sequence variants in the coding region of exon 1 (c. 95 A > T and c. 93 A > T) and two others were previously reported as single-nucleotide polymorphisms (SNPs), namely rs72554028 (c. 2357 G > A) and rs3729753 (c. 606 G > C) in exon 2. Further, observed mutations are completely absent in normal healthy individuals (n = 92). Conclusion: These results suggest that NKX2.5 mutations are highly rare in CHD patients. However, in silico analysis proves that c.95 A > T missense mutation in NKX2.5 gene is probably pathogenic and may be contributing to the risk of sporadic CHD in the Iranian population.

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Section: Discussionmentioning

confidence: 99%

Novel Point Mutations in the NKX2.5 Gene in Pediatric Patients with Non-Familial Congenital Heart Disease

et al. 2018

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“…Tetralogy of Fallot (TF) is a congenital heart defect (CHD), the main anatomical components of which are misplaced aorta, ventricular septal defect, narrowing of the right ventricular (RV) outflow tract, and RV myocardial hypertrophy. TF is a polygenic heart disease resulting from autosomal dominant heterozygous mutations associated with the deletion of a fragment of chromosome 22 (del 22q11.2), and leading to a partial loss of function of transcription factors TBX1 and TBX5, NKX2.5, GATA4.5, 6 [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ], as well as mutations of genes regulating the intracellular signaling pathway of Notch [ 14 , 15 ]. Some patients with TF have trisomy on chromosome 21 (Down syndrome) [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Accelerated Growth, Differentiation, and Ploidy with Reduced Proliferation of Right Ventricular Cardiomyocytes in Children with Congenital Heart Defect Tetralogy of Fallot

Sukhacheva

Серов

Nizyaeva

et al. 2022

Cells

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The myocardium of children with tetralogy of Fallot (TF) undergoes hemodynamic overload and hypoxemia immediately after birth. Comparative analysis of changes in the ploidy and morphology of the right ventricular cardiomyocytes in children with TF in the first years of life demonstrated their significant increase compared with the control group. In children with TF, there was a predominantly diffuse distribution of Connexin43-containing gap junctions over the cardiomyocytes sarcolemma, which redistributed into the intercalated discs as cardiomyocytes differentiation increased. The number of Ki67-positive cardiomyocytes varied greatly and amounted to 7.0–1025.5/106 cardiomyocytes and also were decreased with increased myocytes differentiation. Ultrastructural signs of immaturity and proliferative activity of cardiomyocytes in children with TF were demonstrated. The proportion of interstitial tissue did not differ significantly from the control group. The myocardium of children with TF under six months of age was most sensitive to hypoxemia, it was manifested by a delay in the intercalated discs and myofibril assembly and the appearance of ultrastructural signs of dystrophic changes in the cardiomyocytes. Thus, the acceleration of ontogenetic growth and differentiation of the cardiomyocytes, but not the reactivation of their proliferation, was an adaptation of the immature myocardium of children with TF to hemodynamic overload and hypoxemia.

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“…In recent years, increasing evidence indicates that TOF has high genetic heterogeneity and various genes involved in heart development may be responsible for the phenotype of the disease ( 5 – 7 ). Several previous studies have identified rare potential pathogenic variants of new candidate genes in patients with TOF using whole exome sequencing (WES) such as notch receptor 1 ( NOTCH1 ) ( 7 ), GATA-binding protein 4 ( GATA4 ) ( 8 ), NK2 homeobox 5 ( NKX2.5 ) ( 9 ), Jagged 1 ( JAG1 ) ( 10 ), forkhead box C2 ( FOXC2 ) ( 11 ), T-box 5 ( TBX5 ) ( 12 ), T-box 1 ( TBX1 ) ( 13 ), and Fms-related tyrosine kinase 4 ( FLT4 ) ( 7 ). These findings provide insights into the complex genetic variants responsible for TOF; however, the specific etiology of most TOF cases remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Case Report: Tetralogy of Fallot in a Chinese Family Caused by a Novel Missense Variant of MYOM2

Wang

Xie

et al. 2022

Front. Cardiovasc. Med.

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BackgroundRare genetic variants have been identified to be important contributors to the risk of Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease (CHD). But relatively limited familial studies with small numbers of TOF cases have been reported to date. In this study, we aimed to identify novel pathogenic genes and variants that caused TOF in a Chinese family using whole exome sequencing (WES).MethodsA Chinese family whose twins were affected by TOF were recruited for this study. A WES was performed for the affected twins, their healthy brother, and parents to identify the potential pathogenic mutated gene(s). Heterozygous variants carried by the twins, but not the unaffected brother, were retained. Public databases were used to assess the frequencies of the selected variants, and online prediction tools were accessed to predict the influences of these variants on protein function. The final candidate variant was further confirmed by Sanger sequencing in other members of the family.ResultsAfter several filtering processes, a heterozygous missense variant in the MYOM2 gene (NM_003970.4:c.3097C>T:p.R1033C) was identified and confirmed by Sanger sequencing in the affected twins and their unaffected father, suggesting an inheritance pattern with incomplete penetrance. The variant was found to be extremely rare in the public databases. Furthermore, the mutated site was highly conserved among mammals, and as shown using multiple online prediction tools, this variant was predicted to be a detrimental variant.ConclusionWe assessed a family with TOF caused by a rare heterozygous missense variant of MYOM2. Our findings not only further confirm the significant role of genetics in the incidence of TOF but also expand the spectrum of the gene variants that lead to TOF.

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

Cited by 7 publications

References 38 publications

Novel Point Mutations in the NKX2.5 Gene in Pediatric Patients with Non-Familial Congenital Heart Disease

Novel Point Mutations in the NKX2.5 Gene in Pediatric Patients with Non-Familial Congenital Heart Disease

Accelerated Growth, Differentiation, and Ploidy with Reduced Proliferation of Right Ventricular Cardiomyocytes in Children with Congenital Heart Defect Tetralogy of Fallot

Case Report: Tetralogy of Fallot in a Chinese Family Caused by a Novel Missense Variant of MYOM2

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