Taha Mohamed, Awny Nourhan, Ismail Somaia, Ashaat Engy A, Senousy Mahmoud A
Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Giza, Egypt.
Gene. 2023 Oct 5;882:147660. doi: 10.1016/j.gene.2023.147660. Epub 2023 Jul 20.
Congenital cardiac septal defect (CCSD) is the main type of congenital heart disease and owns a very high mortality rate among newborns. CCSD is controlled by specific transcription factors, including T-box transcription factor 20 (TBX20) and Cbp/P300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2 (CITED2) which are key molecular actors in heart development. Here, we screened for mutations in TBX20 and CITED2 genes in Egyptian children with CCSD and assessed their association with CCSD susceptibility and with cardiac troponin T (cTnT) and the apoptotic marker caspase-3 as biochemical markers for CCSD. Thirty unrelated newborns and children affected with CCSD and 30 matched healthy controls with no personal history of cardiac diseases were recruited. Selection criteria were children (<18 years) with any age diagnosed with CCSD using ECHO. Mutational analysis and genotyping were done using PCR-Sanger DNA sequencing technique. Serum cTnT and caspase-3 were analyzed using ELISA. Sequencing analysis identified 2 TBX20 variants (c.766T>C and c.39T>C) in the CCSD and control groups and 2 CITED2 variants (c.12T>C and c.9C>T) in one CCSD patient, while were absent in controls. In silico analysis identified TBX20 c.766T>C (rs3999941) as a missense (F256L) pathogenic variant and the other three variants as synonymous and benign. Compared with controls, TBX20 c.766T>C TC genotype and minor C allele were candidate high-risk factors for CCSD. Besides, serum cTnT and caspase-3 were dramatically elevated in CCSD children compared to controls. TBX20 c.766T>C TC genotype was associated with high cTnT in CCSD children. Conclusively, we advocate TBX20 c.766T>C variant as a potential genetic marker for CCSD which might associate with high cTnT levels. CITED2 genetic variants might have rare incidence among Egyptian CCSD children. Serum cTnT and caspase-3 are useful markers for ascertaining CCSD in children. These data could be exploited in prenatal genetic counseling, pre-implantation genotyping, and therapy of CCSD.
先天性心脏间隔缺损（CCSD）是先天性心脏病的主要类型，在新生儿中死亡率很高。CCSD由特定转录因子控制，包括T盒转录因子20（TBX20）和富含谷氨酸/天冬氨酸的羧基末端结构域2的Cbp/P300相互作用反式激活因子（CITED2），它们是心脏发育中的关键分子。在此，我们筛查了埃及CCSD患儿TBX20和CITED2基因的突变，并评估了它们与CCSD易感性以及与心肌肌钙蛋白T（cTnT）和凋亡标志物半胱天冬酶-3的关联，将其作为CCSD的生化标志物。招募了30名患有CCSD的无关新生儿和儿童以及30名匹配的无心脏病个人史的健康对照。选择标准为使用超声心动图诊断为CCSD的任何年龄的儿童（<18岁）。使用PCR-桑格DNA测序技术进行突变分析和基因分型。使用酶联免疫吸附测定法分析血清cTnT和半胱天冬酶-3。测序分析在CCSD组和对照组中鉴定出2种TBX20变体（c.766T>C和c.39T>C），在1例CCSD患者中鉴定出2种CITED2变体（c.12T>C和c.9C>T），而在对照组中未发现。生物信息学分析确定TBX20 c.766T>C（rs3999941）为错义（F²⁵⁶L）致病变体，其他三种变体为同义且良性。与对照组相比，TBX20 c.766T>C的TC基因型和次要C等位基因是CCSD的候选高危因素。此外，与对照组相比，CCSD患儿的血清cTnT和半胱天冬酶-3显著升高。TBX20 c.766T>C的TC基因型与CCSD患儿的高cTnT相关。总之，我们主张将TBX20 c.766T>C变体作为CCSD的潜在遗传标志物，它可能与高cTnT水平相关。CITED2基因变体在埃及CCSD患儿中的发生率可能很低。血清cTnT和半胱天冬酶-3是确定儿童CCSD的有用标志物。这些数据可用于产前遗传咨询、植入前基因分型和CCSD的治疗。
