Institute of Microbiology and Molecular Genetics, University of thePunjab, Lahore, 54590, Pakistan.
Ittefaq Trust Hospital, Lahore, Pakistan.
Ital J Pediatr. 2021 Mar 23;47(1):70. doi: 10.1186/s13052-021-01022-7.
Ventricular septal defects (VSDs) are malformations in the septum separating the heart's ventricles. VSDs may present as a single anomaly (isolated/nonsyndromic VSD) or as part of a group of phenotypes (syndromic VSD). The exact location of the defect is crucial in linking the defect to the underlying genetic cause. The number of children visiting cardiac surgery units is constantly increasing. However, there are no representative data available on the genetics of VSDs in Pakistani children.
Two hundred forty-two subjects (121 VSD children and 121 healthy controls) were recruited from pediatric cardiac units of Lahore. The clinical and demographic data of the subjects were collected. A total of four SNPs, one each from MTRR, GATA4, VEGF, and ISL1 genes were genotyped by PCR-RFLP.
The results showed that the minor allele (T) frequency (MAFs) for the MTRR gene variant rs1532268 (c.524C > T) was 0.20 and 0.41 in the controls and the cases, respectively, with the genotype frequencies 3, 35, 62% in the controls and 12, 59 and 29% in the cases for TT, CT, CC genotypes, respectively (allelic OR: 5.73, CI: 3.82-8.61, p-value: 5.11 × 10). For the GATA4 variant rs104894073 (c.886G > A), the MAF for the controls and the cases was 0.16 and 0.37, respectively, the frequencies of AA, GA and GG genotypes were 2, 28, and 70% in the controls and 5, 64 and 31% of the cases (allelic OR: 3.08, CI: 2.00-4.74, p-value: 8.36 × 10). The rs699947 (c.-2578C > A) of VEGF gene showed MAF 0.36 and 0.53 for the controls and cases, respectively, with the genotype frequencies 13, 42, and 45% in the controls and 22, 15, and 63% in the cases for the AA, CA, CC (allelic OR: 2.03, CI: 1.41-2.92, p-value: 0.0001). The ISL1 gene variant rs6867206 (g.51356860 T > C), the MAFs were 0.26 and 0.31 in the controls and cases, respectively. The genotype frequencies were 48, 52, 0% in the controls and 39, 61, 0% in the cases for TT, TC, CC genotypes (allelic OR: 0.27, CI: 0.85-1.89, p-value: 0.227). The MTRR, GATA4 and VEGF variants showed association while ISL1 variant did not appear to be associated with the VSD in the recruited cohort.
This first report in Pakistani children demonstrates that single nucleotide polymorphisms in genes encoding transcription factors, signaling molecules and structural heart genes involved in fetal heart development are associated with developmental heart defects., however further work is needed to validate the results of the current investigation.
室间隔缺损（VSD）是分隔心脏心室的间隔畸形。VSD 可能表现为单一异常（孤立/非综合征性 VSD）或作为一组表型的一部分（综合征性 VSD）。缺陷的确切位置对于将缺陷与潜在的遗传原因联系起来至关重要。到心脏外科单位就诊的儿童人数不断增加。然而，目前还没有关于巴基斯坦儿童 VSD 遗传学的代表性数据。
从拉合尔儿科心脏单位招募了 242 名受试者（121 名 VSD 儿童和 121 名健康对照）。收集了受试者的临床和人口统计学数据。使用 PCR-RFLP 技术对来自 MTRR、GATA4、VEGF 和 ISL1 基因的四个 SNP（每个基因一个）进行了基因分型。
结果表明，MTRR 基因变体 rs1532268（c.524C > T）的次要等位基因（T）频率（MAF）在对照组和病例组中分别为 0.20 和 0.41，基因型频率分别为 3、35、62%在对照组和 12、59 和 29%在病例组中为 TT、CT、CC 基因型（等位基因 OR：5.73，CI：3.82-8.61，p 值：5.11×10）。对于 GATA4 变体 rs104894073（c.886G > A），对照组和病例组的 MAF 分别为 0.16 和 0.37，AA、GA 和 GG 基因型的频率分别为 2、28 和 70%在对照组和 5、64 和 31%的病例（等位基因 OR：3.08，CI：2.00-4.74，p 值：8.36×10）。VEGF 基因的 rs699947（c.-2578C > A）在对照组和病例组中的 MAF 分别为 0.36 和 0.53，基因型频率分别为 13、42 和 45%在对照组和 22、15 和 63%在病例组中的 AA、CA、CC（等位基因 OR：2.03，CI：1.41-2.92，p 值：0.0001）。ISL1 基因变体 rs6867206（g.51356860 T > C）的 MAF 在对照组和病例组中分别为 0.26 和 0.31。基因型频率分别为 48、52、0%在对照组和 39、61、0%在病例组为 TT、TC、CC 基因型（等位基因 OR：0.27，CI：0.85-1.89，p 值：0.227）。MTRR、GATA4 和 VEGF 变体与 VSD 相关，而 ISL1 变体似乎与研究队列中的 VSD 无关。
这是在巴基斯坦儿童中进行的第一项报告，表明编码转录因子、信号分子和结构心脏基因的基因中的单核苷酸多态性与胎儿心脏发育过程中的发育性心脏缺陷有关。然而，需要进一步的工作来验证当前研究结果。
