Congenital Heart Defects, Multiple Types, 4

A number sign (#) is used with this entry because of evidence that multiple types of congenital heart defects (CHTD4) are caused by heterozygous mutation in the NR2F2 gene (107773) on chromosome 15q26.

For a discussion of genetic heterogeneity of multiple types of congenital heart defects, see 306955.

Al Turki et al. (2014) performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic atrioventricular septal defects (AVSDs, see 606215) and identified 5 rare missense mutations in the highly conserved NR2F2 gene (see, e.g., 107773.0001 and 107773.0002), representing significant enrichment compared to 5,194 controls (p = 7.7 x 10(-7)). In other patient cohorts with non-AVSD congenital heart disease (CHD), they identified 3 additional CHD-affected families with other variants in NR2F2. These included a 3-bp duplication (107773.0003) that segregated with CHD in a multiplex family in which 2 affected brothers had AVSD and aortic stenosis with ventricular septal defect (VSD, see 614429), respectively, and their father had tetralogy of Fallot (see 187500); a de novo substitution disrupting a splice donor site (107773.0004) in a patient with hypoplastic left heart syndrome (see 241550); and a de novo balanced chromosomal translocation 46,XY,t(14;15)(q23;q26.3) in a patient with coarctation of the aorta and other developmental anomalies who was previously studied by Baptista et al. (2008). The translocation was fine-mapped to the first intron of NR2F2, with the breakpoint predicted to truncate all annotated transcripts and generate a null allele. All 6 coding sequence variants significantly altered the activity of NR2F2 on target promoters.