image: This study conducted a comprehensive WGS analysis of 354 CHD trios of Chinese ethnic origin to identify novel CHD-related genes, and provided important insights into the roles of these genes in heart development and the pathogenesis of CHD through a multi-level systematic analysis.
Credit: ©Science Bulletin
Congenital heart disease (CHD) represents the most common type of birth defect and remains the leading cause of death in neonates and infants. The role of genetic factors in the development of CHD has increasingly been recognized. To date, large cohort studies on CHD-associated pathogenic genes have primarily focused on European and American populations, while large-scale studies in Asian populations remain relatively scarce. This knowledge gap has limited the comprehensive understanding of the genetic mechanisms underlying congenital heart disease.
In this study, 393 de novo coding variants were detected, among which 16 met the pathogenic classification criteria established by the American College of Medical Genetics and Genomics (ACMG). Combining two de novo variant prioritization methods, they identified 11 overlapping candidate genes. Among these, three genes – PTPN11, SETD2, and RASAL2 – showed high expression levels in single-cell RNA sequencing data from early fetal heart development. Notably, this study also discovered a potentially pathogenic non-coding de novo single nucleotide variant (chr18:24040823), which can regulate the expression of SOX13 and subsequently lead to disease development. Meanwhile, compound heterozygous single nucleotide variants in both LAMA5 and SCN4A were observed in multiple families. Additionally, the study identified a pathogenic de novo large segmental duplication containing the YWHAE gene. YWHAE is an unreported novel gene associated with heart development that may be involved in the pathogenesis of congenital heart disease. More importantly, by further integrating single-cell data from congenital heart disease patients with phenotypic databases from animal models, this study screened 25 novel genes associated with abnormal cardiovascular phenotypes, suggesting that these genes may play important roles in the development of congenital heart disease.
Overall, this study not only systematically maps the coding and non-coding variant landscape of CHD in an Asian population, but also identifies multiple novel potential pathogenic genes and their genetic regulatory mechanisms. This work provides important new clues for understanding the genetic basis of CHD and heart development, and lays a critical foundation for clinical genetic testing and genetic counseling of birth defects in the Chinese population.
Journal
Science Bulletin