Genetic Abnormalities in FOXP1 Are Associated with Congenital Heart Defects

The etiology for the majority of congenital heart defects ( CHD ) is unknown. We identified a patient with unbalanced atrioventricular septal defect ( AVSD ) and hypoplastic left ventricle who harbored an ∼0.3 Mb monoallelic deletion on chromosome 3p14.1. The deletion encompassed the first four exons of FOXP1 , a gene critical for normal heart development that represses cardiomyocyte proliferation and expression of N kx2.5. To determine whether FOXP1 mutations are found in patients with CHD , we sequenced FOXP1 in 82 patients with AVSD or hypoplastic left heart syndrome. We discovered two patients who harbored a heterozygous c.1702 C > T variant in FOXP1 that predicted a potentially deleterious substitution of a highly conserved proline (p. P ro568 S er). This variant was not found in 287 controls but is present in db SNP at a 0.2% frequency. The orthologous murine F oxp1 p. P ro596 S er mutant protein displayed deficits in luciferase reporter assays and resulted in increased proliferation and N kx2.5 expression in cardiomyoblasts. Our data suggest that haploinsufficiency of FOXP1 is associated with human CHD .