Identification and pathological significance of variants in the promoter region of ACTC1 gene in congenital ventricular septal defect

Ventricular septal defect (VSD) is one of the most common congenital heart diseases, but the role of variants at the ACTC1 gene promoter region in VSD is unclear. We investigated variants in the promoter region of ACTC1 gene in 627 subjects (309 sporadic VSD patients and 318 healthy controls) by Sanger sequencing and 6 variants including 1 novel heterozygous variant [g.5163 T > A] were identified. Of the 6 variants, 3 were found only in VSD patients. In mouse cardiomyocytes (HL-1), the transcriptional activity of the ACTC1 gene promoter was significantly changed by the variants (p < 0.05). Electrophoretic mobility shift assay results and JASPAR database analysis indicated that these variants may affect the transcription of the ACTC1 gene by influencing the binding ability of transcription factors, thus potentially contributing to the formation of VSD. This study provides a new perspective for the genetic and molecular mechanism of variants of the promoter region of ACTC1 gene in the pathogenesis of VSD.