文摘
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 m>NR2F2m>, a very significant enrichment (p = 7.7聽脳 10鈭?) compared to 5,194 control subjects. We identified three additional CHD-affected families with other variants in m>NR2F2m> including a de novo balanced chromosomal translocation, a de novo substitution disrupting a splice donor site, and a 3聽bp duplication that cosegregated in a multiplex family. m>NR2F2m> encodes a pleiotropic developmental transcription factor, and decreased dosage of m>NR2F2m> 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.