Although congenital heart defects (CHD) are the most common and serious group of birth defects, relatively little is known about the causes of these conditions and there are no established prevention strategies. There is evidence suggesting that the risk of CHD in general, and conotruncal and ventricular septal defects in particular, may be related to maternal folate status as well as genetic variants in folate-related genes. However, efforts to establish the relationships between these factors and CHD risk have been hampered by a number of factors including small study sample sizes and phenotypic heterogeneity.

The present study examined the relationships between variation in 9 folate-related genes and a subset of CHD phenotypes (ie, conotruncal defects, perimembranous and malalignment type ventricular septal defects, and isolated aortic arch anomalies) in a cohort of >700 case-parent triads. Further, both maternal and embryonic genetic effects were considered. Analyses of the study data confirmed an earlier reported association between embryonic genotype for MTHFR A1298C and disease risk (unadjusted P=0.002).

These results represent the most comprehensive and powerful analysis of the relationship between CHD and folate-related genes reported to date, and provide additional evidence that, similar to neural tube defects, this subset of CHD is folate related.