Content area
Full text
Background
Ventricular septal defects (VSDs) are forms of congenital cardiac disease that contribute to 40% of mortality in the first month of childbirth [1, 2]. The reported frequency VSDs is 2.62 to 3.5/1000 live births in the Asian population. In the Pakistani population, VSDs constitutes 40% of the overall cardiac disease and is reported in 30–34% of congenital heart disease (CHD) patients [1]. The high frequency of disease, especially in infants, poses a significant disease burden and a challenge to disease management especially in developing countries. A broad range of genetic mechanisms are either strongly suspected or known to participate in causing VSDs. Like most traits that exhibit complex inheritance, there are still many unknowns and the relative importance of various genetic factors (common variants, rare variants, copy number variations (CNVs), de novo mutations, epistasis, epigenetics, etc.) remains to be identified [3, 4]. Higher heritability of congenital heart defects like VSDs means that genetic determinants have a crucial role in the overall occurrence of these defects in the population and that the combined impact of genetic factors is possibly far larger than all environmental factors aggregated. The etiology of VSDs is the same as other cardiovascular diseases that include a combination of environmental and genetic factors. Mutations or genetic variations in various regulators, transcription factors and enzymes that play a role in heart development are associated with the VSDs phenotype [5, 6]. Mutations or genetic variations in various regulators, transcription factors, and enzymes that play a role in heart development are associated with the VSDs phenotype. Other environmental factors like, maternal infections during pregnancy, exposure to teratogens, consanguinity and hypoxia during pregnancy can also contribute for vsds. Despite their importance, the studies focused on VSDs in pediatric patients are still underreported in the Pakistani population [7]. Current research largely focuses on environmental and genetic contributions to VSDs at a global level, yet there is limited understanding of how genetic variations specifically influence VSD susceptibility in populations with high consanguinity, such as Pakistan. Furthermore, few studies have utilized polygenic risk score (PRS) analysis to assess the cumulative effect of multiple genetic variants associated with VSDs in this population. Addressing this gap is crucial, as it can provide unique insights into the genetic etiology of VSDs in...