Identifying Pathogenic Variants in Vietnamese Children with Functional Single Ventricle Based on Whole-Exome...

Background: Functional single ventricle (FSV) comprises a heterogeneous group of congenital heart diseases (CHDs) with severe and complex abnormalities. The multifactorial etiology of the disease poses challenges in identifying specific pathogenic factors and planning effective interventions and preventive treatments for patients. Methods: Whole-exome sequencing (WES) was performed to identify variants in relevant genes in 29 FSV patients from different families. Results: In total, 95 heterozygous variants across 48 CHD-associated genes were identified, including 85 missense, four small indel, one splicing, one stop gain, and four synonymous variants. Among them, 22 were novels, 11 conflicting, and four pathogenic variants. Each patient carried from two to six variants in different genes, including at least one variant in genes associated with serious heart defects such as AXIN1, BMP2, COL6A2, GATA4, GATA5, GDF1, MESP1, MYH6, NFATC1, NKX2-6, NOTCH1, PCSK9, TBX1, TBX18, and TBX20. In addition, the variants in the COL6A1, CREBBP, DOCK6, EOGT, EP300, LRP2, MYBPC3, MYH7, SEMA3C, and ZFPM2 genes are associated with characteristic phenotypes of FSV, such as atrial septal defect, ventricular septal defect, small left heart syndrome, transposition of the great arteries, and double outlet right ventricle occurring at high frequency in patients. The prediction results suggest that these are potentially pathogenic variants in patients and may explain the phenotype in patients. Conclusions: This is the first study to identify variants associated with functional single ventricle, a complex form of congenital heart disease. Our results contribute to a general understanding of the causes of the disease, thereby guiding treatment and prevention approaches for patients.