SDHC Gene is a Potential Player in the Pathogenesis of Congenital Heart Disease and Neurodevelopmental Disorder by Promoting eNOS Signaling, Suppressing Inflammation and Improving Angiogenic Endothelial Function
Xinmei Deng, Yuanqin Zhao, Wei Deng, Zhaoyue Wang, Kun Zhou, Qian Xu, Xiang Li, Xinyi Qin, Liyuan Guo, Youze Tan, Yisong Qian, Yunbin Xiao, Zhi-Sheng JiangIntroduction:
Congenital Heart Disease (CHD) and Neurodevelopmental Disorders (NDD) frequently co-occur due to shared genetic defects in embryonic angiogenesis and mitochondrial metabolism; however, the regulatory mechanisms linking these pathways remain poorly understood.
Objective:
To identify pathogenic genes underlying CHD-NDD co-development and investigate the regulatory role of Succinate Dehydrogenase Complex Subunit C (SDHC) in endothelial angiogenesis.
Methods:
Blood samples from 70 children (13 CHD+NDD, 33 CHD, 24 NDD) were analyzed by Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS). Candidate genes were identified through bidirectional deduplication, multi-library comparison, PPI network analysis, and functional enrichment analysis. SDHC expression was examined by immunofluorescence in the developing mouse heart and brain. In Human Umbilical Vein Endothelial Cells (HUVECs) with SDHC overexpression or knockdown, eNOS and TNF-α protein levels were measured by Western blot. Cell migration and tube formation were quantified by scratch and Matrigel assays.
Results:
WES identified high-frequency SDHC mutations, including T→TTA (Chr1:161293485, 33.33%) and C→CT (Chr1:161332091, 55.56%) in CHD+NDD. Bioinformatics suggested SDHC involvement in cardiac and neural development. In mice, cardiac SDHC increased age-dependently by 71.83% (P < 0.05), 100.21% (P < 0.01), and 239.89% (P < 0.0001) from 1 to 8 weeks. In HUVECs, SDHC overexpression upregulated eNOS by 103.25% (P < 0.001) and downregulated TNF-α by 45.16% (P < 0.01); knockdown downregulated eNOS by 43.37% (P < 0.05). SDHC overexpression increased migration by 42.96% (P < 0.0001), while its knockdown decreased it by 34.02% (P < 0.001). Tube formation nodes increased by 130.24% (P < 0.0001) and mesh area by 111.82% (P < 0.0001); knockdown reduced mesh area by 80.81% (P < 0.0001).
Discussion:
These findings suggest SDHC dysregulation may affect CHD-NDD comorbidity through eNOS modulation and inflammatory responses in HUVECs. The presence of SDHC variants in 7 of 13 patients (53.8%) and functional data indicate SDHC may serve as a candidate angiogenesis regulator linking cardiovascular and neurodevelopmental abnormalities. However, the small cohort (n = 13 CHD + NDD), absence of healthy controls, and lack of patient-derived variant validation limit definitive conclusions. The biological consequences of the identified variants remain unknown because variant-specific functional analyses were not performed. Future studies require expanded cohorts and in vivo SDHC- specific models to investigate potential associations.
Conclusion:
SDHC may play potential roles in eNOS signaling, inflammation suppression, and endothelial angiogenic function. These findings suggest SDHC as a candidate gene associated with CHD-NDD comorbidity.