De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects

Abstract

Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk.

Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease

“…Diabetes mellitus is associated with a multitude of metabolic disturbances, and elevated glucose levels appear to be the primary teratogen for diabetic embryopathy (12). Consistent with this, improved glucose control during pregnancy is associated with reduction in CHD risk and, alternatively, poor glycemic control is linked to a higher risk for CHD in offspring (10).…”

“…Studies of genetic contributors have identified an increasing number of genes associated with CHD (7)(8)(9). The importance of gene dosage for the occurrence of cardiac malformations has been shown, along with the concept of an oligogenic etiology for CHD, supporting the concept that mild alterations in gene expression levels may lead disease phenotypes (10)(11)(12)(13). Similarly, numerous environmental risk factors for CHD have been reported, each of which increases the risk of having a child with CHD (14).…”

Genetics and Genomics of Congenital Heart Disease

“…Notably, de novo mutations accounted for at least 20% of CHD with associated extracardiac and neurodevelopmental abnormalities 75 . While these mutations are more prominently associated with syndromic rather than non-syndromic CHD 80 , there is a small but measurable contribution to isolated CHD (CHD not associated with a known syndrome, and without any extracardiac malformations or neurodevelopmental abnormalities) 81 , which may become more clearly delineated when larger cohorts are analyzed 8275 .…”

Comparison of Echocardiography and 64-Multislice Spiral Computed Tomography for the Diagnosis of Pediatric Congenital Heart Disease

“…CHD is caused by many factors, including intrauterine infection, environmental pollution, and inheritable factors [2]. It was reported that the primary cause of mortality from birth defects was related to the structure or function of the heart lesion [3].…”