Yan Zi, Dong Bin-Bin, Li Yan-Jie, Yang Chen-Xi, Xu Ying-Jia, Huang Ri-Tai, Liu Xing-Yuan, Yang Yi-Qing
Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
Department of Pediatrics, Huashan Hospital, Fudan University, Shanghai 200040, China.
Children (Basel). 2025 May 7;12(5):608. doi: 10.3390/children12050608.
Congenital heart disease (CHD) occurs in ~1% of all live neonates globally, rendering it the most prevalent developmental anomaly affecting humans; this condition confers substantial infant morbidity and mortality worldwide. Although there is ample evidence to suggest a paramount genetic basis for CHD, the genetic etiologies underpinning the majority of CHD remain elusive. In the present study, was selected as a significant candidate gene for human CHD, mainly because SOX4 is abundantly expressed in both human and murine hearts during embryogenesis, and the knockout of in mice causes embryonic demise predominantly attributable to cardiovascular developmental defects. Sequencing analysis of was fulfilled in 248 probands affected with various types of CHD and the available relatives of the identified variation carrier as well as 262 unrelated healthy individuals. Functional analysis of the mutant SOX4 protein was conducted by utilizing a dual-reporter gene system. a novel heterozygous variation, NM_003107.3:c.331G>T;p.(Glu111*), was discovered in a male proband with Coffin-Siris syndromic CHD. Genetic investigation of the proband's available relatives revealed that the truncating variation co-segregated with the phenotype in the whole family. The nonsense variation was absent from 262 healthy controls. Functional analysis demonstrated that the Glu111*-mutant SOX4 lost transactivation on and , two well-established genes that are causative factors for CHD. Moreover, the Glu111* mutation nullified the synergistic transactivation between SOX4 and TBX20, another CHD-causing gene. These findings support as a causative gene accountable for familial Coffin-Siris syndromic CHD in humans. These findings may aid in developing personalized preventive and therapeutic strategies for patients with Coffin-Siris syndromic CHD.
先天性心脏病（CHD）在全球所有活产新生儿中的发生率约为1%，使其成为影响人类的最常见发育异常；这种疾病在全球范围内导致大量婴儿发病和死亡。尽管有充分证据表明CHD有重要的遗传基础，但大多数CHD的遗传病因仍不清楚。在本研究中，SOX4被选为人类CHD的一个重要候选基因，主要是因为SOX4在胚胎发育过程中在人类和小鼠心脏中均大量表达，并且在小鼠中敲除SOX4会导致胚胎死亡，主要归因于心血管发育缺陷。对248例患有各种类型CHD的先证者及其已鉴定变异携带者的可用亲属以及262名无关健康个体进行了SOX4测序分析。利用双报告基因系统对突变型SOX4蛋白进行了功能分析。在一名患有科芬-西里斯综合征相关CHD的男性先证者中发现了一种新的杂合SOX4变异，NM_003107.3:c.331G>T;p.(Glu111*)。对该先证者可用亲属的基因调查显示，这种截短变异在整个家族中与表型共分离。262名健康对照中未发现这种无义变异。功能分析表明，Glu111突变型SOX4失去了对GATA4和TBX20的反式激活作用，这两个已确定的基因是CHD的致病因素。此外，Glu111突变消除了SOX4与另一个CHD致病基因TBX20之间的协同反式激活作用。这些发现支持SOX4作为人类家族性科芬-西里斯综合征相关CHD的致病基因。这些发现可能有助于为患有科芬-西里斯综合征相关CHD的患者制定个性化的预防和治疗策略。
