Conotruncal heart defects (CTDs) are heart malformations that affect the cardiac outflow tract and typically cause significant morbidity and mortality. Evidence from epidemiological studies suggests that maternal folate intake is associated with a reduced risk of heart defects, including CTD. However, it is unclear if folate-related gene variants and maternal folate intake have an interactive effect on the risk of CTDs. In this study, we performed targeted sequencing of folate-related genes on DNA from 436 case families with CTDs who are enrolled in the National Birth Defects Prevention Study and then tested for common and rare variants associated with CTD. We identified risk alleles in maternal MTHFS (OR_meta = 1.34; 95% CI 1.07 to 1.67), maternal NOS2 (OR_meta = 1.34; 95% CI 1.05 to 1.72), fetal MTHFS (OR_meta = 1.35; 95% CI 1.09 to 1.66), and fetal TCN2 (OR_meta = 1.38; 95% CI 1.12 to 1.70) that are associated with an increased risk of CTD among cases without folic acid supplementation. We detected putative de novo mutations in genes from the folate, homocysteine, and transsulfuration pathways and identified a significant association between rare variants in MGST1 and CTD risk. Results suggest that periconceptional folic acid supplementation is associated with decreased risk of CTD among individuals with susceptible genotypes.

A 69-year-old woman with hypothyroidism, sarcoidosis, and recently diagnosed serous ovarian cancer presented to the emergency department with generalized weakness, dyspnea, and poor oral intake during the prior week. The patient was admitted to the intensive care unit with presumed sepsis. Imaging revealed liver and omental metastases with large-volume ascites. Work-up showed pancytopenia, hypoalbuminemia, and increased liver enzymes. A lipid panel from …