Molecular Characterization of two NR2F2 Exons identifies a Rare Intronic Variant Enriched in Indonesian Congenital Heart Disease Patients

Abstract

Background: Congenital heart disease is a globally prevalent congenital disorder that has a complicated genetic etiology that includes both coding and non-coding variants. Although there is much evidence of pathogenic coding variants in key transcription factors, the role of regulatory variants in the Indonesian population is less known. The NR2F2 plays an essential role in cardiac development. To determine potentially pathogenic variation, we performed a case-control genetic study in Indonesian patients with CHD to find variants in the NR2F2 gene.Methods: 27 ethnically matched controls and 35 CHD patients were examined, and genomic DNA was extracted from peripheral blood samples. Following targeted Sanger sequencing to identify potential pathogenic variants in exons 2 and 3 of the NR2F2 gene, extensive bioinformatic annotation was carried out using genomic visualization platforms.Results: This study identified a rare intronic variation of the NR2F2 gene, rs753513812 (c.970+11G>C; g.8677G>C), in eight of 35 CHD patients, and it was absent in all control individuals and the majority of CHD subtypes. The variation was significantly enriched in CHD patients. This finding suggests that CHD susceptibility may play a role through non coding regulatory variations. Among the 35 patients examined, no pathogenic or likely pathogenic variants were detected in exons 2 and 3 of the NR2F2 gene.Conclusion: These findings imply that pathogenic coding variants within these exons are unlikely to be a frequent genetic cause of CHD in Indonesian patients. Also, the study highlights the need for population-specific genetic investigations and their contribution to human cardiac development.