Rare variants in NR2F2 cause congenital heart defects in humans.

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.

Personalized medicine in pediatric cardiology: do little changes make a big difference?

PURPOSE OF REVIEW: Advances in genomics have paved the way for personalized medicine applications. This review will discuss new discoveries in genomics and pharmacogenomics in children with congenital heart disease (CHD) and the application towards the development of new diagnostics, disease risk predictions, and optimizing response to drugs and surgery. RECENT FINDINGS: Recent advances have identified common and rare variants associated with complex CHD using next-generation sequencing and genotyping technology. Next-generation sequencing is now being used not only for clinical genetic testing but also for noninvasive prenatal testing of fetal DNA in maternal serum to diagnose genetic conditions like fetal aneuploidies as early as the first trimester. This approach is not only more accurate but also safer than invasive maternal screening tests. This technology may also help in noninvasive diagnosis of transplant rejection. As genetic variations that influence the response to surgery in CHD are identified, this can guide decision-making surrounding optimum type and timing of surgery. Drug choice and dosing are being increasingly influenced by knowledge of pharmacogenetic and pharmacodynamic variations. Age-related and maturation-related changes in drug pharmacokinetics make it crucial to perform pediatric-targeted pharmacogenetic studies to enable the incorporation of age into genotype-guided drug dosing algorithms. SUMMARY: Rapid genomic and pharmacogenomic discovery are guiding the development of more sensitive screening and diagnostic tests for CHD as well as development of safer and more effective drugs. This needs to be paralleled by the development of strategies to support rapid translation of emerging genomic knowledge to patient care.