Title: Genetic variants of the CITED2 gene promoter in sporadic tetralogy of fallot patients with clinical implications
Abstract:
Background: Tetralogy of Fallot (TOF) is a common congenital heart malformation. Genetic variants in the CITED2 coding region is known to be significantly associated with cardiac malformation, but the role of variants in the CITED2 promoter region in the development of TOF remains unclear.
Methods: In this study, we investigated CITED2 promoter variants in the DNA of 605 subjects, including 312 TOF patients and 293 unrelated healthy controls, by Sanger sequencing. The discovered variants were further verified by cellular functional studies to examine the pathological role. JASPAR database analysis was used to predict the possible transcription factor binding sites that may result in changes in CITED2 protein expression.
Results: We identified nine CITED2 gene promoter variants (including one novel heterozygous variant). Six were found only in patients with TOF and none in the control group. The transcriptional activity of CITED2 gene promoter in mouse cardiomyocytes (HL-1) was significantly altered by the 6 variants (P<0.05). The results of electrophoretic mobility change assay and JASPAR database analysis showed that these variants generated or destroyed a series of possible transcription factor binding sites, resulting in changes in CITED2 protein expression.
Conclusion: We conclude that CITED2 promoter variants in TOF patients affect transcriptional activity and may be involved in the occurrence and progression of TOF. These findings may provide new insights into molecular pathogenesis and potential therapeutic insights of precision medicine in patients with TOF.
Audience Take Away Notes:
- The audience will be able to use genetic knowledge in the diagnosis of congenital heart disease
- To help precision diagnosis of tetralogy of Fallot.
- To help other faculties enhancing genetic studies in congenital diseases.
- Will improve the accuracy of diagnosis of congenital heart disease.
- Will help understanding the role of gene promoter in physiology and pathophysiology of diseases.
