Background. Atrial septal defect (ASD), one of the most prevalent congenital cardiac malformations, has a well-established link to genetic factors. ACTC1 gene plays important role in the development of the heart but the genetic variants within the proximal promoter region of the ACTC1 gene in ASD pathogenesis are unclear. This case-control study aimed to investigate the variants of proximal promoter region of the ACTC1 in ASD patients. Methods. We extracted genomic DNA from blood samples of 634 subjects (316 ASD patients and 318 matched healthy controls) and conducted sequencing of the ACTC1 proximal promoter region. To assess the functional impact of these variants, we carried out in vitro dual-luciferase reporter assays. To further reveal the molecular mechanism, we employed electrophoretic mobility shift assays (EMSAs) and performed in silico predictions of the protein’s binding affinity using the JASPAR database. Results. Our analysis identified 11 variants in the proximal promoter region. Six of these were exclusively found in ASD patients, one of which was a novel variant (g.5083G>A). The results indicated that all six variants led to a significant reduction in proximal promoter transcriptional activity (p < 0.05). An integrated analysis revealed that these variants disrupt or alter specific transcription factor binding sites, thereby interfering with the normal transcriptional regulation of the ACTC1 gene. Conclusions. Our study identifies a novel mechanism in which ACTC1 proximal promoter variants impair gene transcription by disrupting transcription factor binding. These findings provide new experimental evidence and a theoretical basis for the genetic etiology of ASD.
- Open Access
- Article
Genetic Variants with Cellular Dysfunction and Pathogenic Significance of ACTC1 Gene Proximal Promoter in 634 Patients with Atrial Septal Defects and Controls
- Zi-Fei Zheng 1,2,3,4,†,
- Huan-Xin Chen 1,2,3,4,†,
- Hai-Tao Hou 1,2,3,4,†,
- Qin Yang 1,2,3,4,†,
- Guo-Wei He 1,2,3,4,*
Author Information
Received: 13 Feb 2026 | Revised: 15 Apr 2026 | Accepted: 13 May 2026 | Published: 05 Jun 2026
Abstract
Graphical Abstract
Keywords
atrial septal defect | ACTC1 | genetic | congenital heart disease
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