BACKGROUND: Congenital heart disease (CHD) is the most common anomaly at birth, with
a prevalence of approximate to 1%. While infants born to mothers with diabetes or
obesity have a 2- to 3-fold increased incidence of CHD, the cause of the increase
is unknown. Damaging de novo variants (DNV) in coding regions are more common among
patients with CHD, but genome-wide rates of coding and noncoding DNVs associated with
these prenatal exposures have not been studied in patients with CHD. METHODS: DNV
frequencies were determined for 1812 patients with CHD who had whole-genome sequencing
and prenatal history data available from the Pediatric Cardiac Genomics Consortium's
CHD GENES study (Genetic Network). The frequency of DNVs was compared between subgroups
using t test or linear model. RESULTS: Among 1812 patients with CHD, the number of
DNVs per patient was higher with maternal diabetes (76.5 versus 72.1, t test P=3.03
x 10(-11)), but the difference was no longer significant after including parental
ages in a linear model (paternal and maternal correction P=0.42). No interaction was
observed between diabetes risk and parental age (paternal and maternal interaction
P=0.80 and 0.68, respectively). No difference was seen in DNV count per patient based
on maternal obesity (72.0 versus 72.2 for maternal body mass index <25 versus maternal
body mass index >30, t test P=0.86). CONCLUSIONS: After accounting for parental age,
the offspring of diabetic or obese mothers have no increase in DNVs compared with
other children with CHD. These results emphasize the role for other mechanisms in
the cause of CHD associated with these prenatal exposures.
