Abstract
Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Nonsyndromic atrioventricular septal defects (AVSDs) are an important subtype of CHDs for which the genetic architecture is poorly understood. We performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic AVSDs and identified five rare missense variants (two of which arose de novo) in the highly conserved gene NR2F2, a very significant enrichment (p = 7.7 × 10(-7)) compared to 5,194 control subjects. We identified three additional CHD-affected families with other variants in NR2F2 including a de novo balanced chromosomal translocation, a de novo substitution disrupting a splice donor site, and a 3 bp duplication that cosegregated in a multiplex family. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. Via luciferase assays, we showed that all six coding sequence variants observed in individuals significantly alter the activity of NR2F2 on target promoters.
Highlights
Fewer than 20% of congenital heart defects (CHDs) can be attributed to large structural chromosomal variants or single-gene mutations causing monogenic syndromes.[1]
In the current study we report an enrichment of likely causal variants in NR2F2 in families with isolated atrioventricular septal defects (AVSDs) as well as other isolated Congenital heart defects (CHDs) phenotypes including coarctation of aorta (CoA [MIM 120000])
NGFI-A,30 to drive a luciferase reporter in HEK293 cells, we compared its level of activation by wild-type NR2F2 with that of the case-derived variants
Summary
Fewer than 20% of congenital heart defects (CHDs) can be attributed to large structural chromosomal variants or single-gene mutations causing monogenic syndromes.[1] The majority of CHDs are nonsyndromic (individuals without extracardiac phenotypes) and are of unknown etiology.[2] Mouse knockout studies have identified more than 300 genes in which (typically homozygous) loss-of-function mutations are sufficient to cause CHDs, and, given that only a minority of genes have been knocked out in mice far, hundreds more genes essential for cardiac development remain to be identified.[3].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
