Behiry Eman G, Al-Azzouny Mahmoud A, Sabry Dina, Behairy Ola G, Salem Nessrine E
Clinical and Chemical Pathology Department, Benha Faculty of Medicine, Benha University, Benha, Egypt.
Biochemistry Department, Cairo Faculty of Medicine, Cairo University, Cairo, Egypt.
Mol Genet Genomic Med. 2019 May;7(5):e612. doi: 10.1002/mgg3.612. Epub 2019 Mar 4.
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.
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.
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.
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.
已知几个编码转录因子的基因是先天性心脏病的主要病因。NKX2 - 5和GATA4是通过连锁分析鉴定出的首批先天性心脏病致病基因。本研究旨在探讨NKX2 - 5、GATA4和TBX5基因的五个单核苷酸变异与埃及儿童散发性非综合征型先天性心脏间隔缺损病例之间的关联。
对150例先天性心脏病儿童（包括室间隔缺损、房间隔缺损、法洛四联症和动脉导管未闭）以及90例年龄和性别匹配的明显健康儿童采集静脉血样，采用聚合酶链反应随后直接测序的方法，以研究NKX2 - 5的两个单核苷酸变异（rs2277923、rs28936670）、GATA4的两个单核苷酸变异（rs368418329、rs56166237）和TBX5的一个单核苷酸变异（rs6489957）。分析先天性心脏病（CHD）组和对照组中基因型和等位基因频率的分布。
我们发现NKX2 - 5两个变异的基因型频率不同，rs2277923的CT基因型在病例组和对照组中的比例分别为58%和36%，TT基因型在病例组中占6%。同样，对于错义变异rs28936670，杂合子AG在病例组中占82%。此外，我们观察到一个5'非翻译区变异rs368418329，GT（病例组中的比例为42%）和GG（病例组中的比例为46%）基因型在病例组中出现频率最高。而对于同义变异rs56166237，GT和GG在病例组中出现最多（分别为41.4%、56%）相比对照组（分别为20%、1.7%）。同样，TBX5中的一个同义变异，基因型频率分布在CHD组和对照组之间存在显著差异。TBX5 - rs6489957的CT基因型在12例房间隔缺损、24例室间隔缺损、6例动脉导管未闭、3例主动脉缩窄和9例法洛四联症中被发现，占病例的42%。
与对照组相比，病例组中五个变异的不同等位基因频率显著更高，对间隔缺损的发生具有显著的风险效应。除了心脏间隔缺损中NKX2 - 5的两个多态性（rs2277923、rs28936670）变异外，GATA4的两个变异（rs368418329、rs56166237）和TBX5的一个变异（rs6489957）似乎在先天性心脏病的发病机制中起作用。
