Communicated by Reed E. Pyeritz
Genetic Abnormalities in FOXP1 Are Associated with Congenital Heart Defects
Article first published online: 11 JUL 2013
© 2013 WILEY PERIODICALS, INC.
Volume 34, Issue 9, pages 1226–1230, September 2013
How to Cite
Chang, S.-W., Mislankar, M., Misra, C., Huang, N., DaJusta, D. G., Harrison, S. M., McBride, K. L., Baker, L. A. and Garg, V. (2013), Genetic Abnormalities in FOXP1 Are Associated with Congenital Heart Defects. Hum. Mutat., 34: 1226–1230. doi: 10.1002/humu.22366
Contract grant sponsors: American Pediatric Society/Society of Pediatric Research Student Research Program; Children's Heart Foundation and the Research Institute at Nationwide Children's Hospital.
- Issue published online: 14 AUG 2013
- Article first published online: 11 JUL 2013
- Accepted manuscript online: 13 JUN 2013 07:18AM EST
- Manuscript Accepted: 3 JUN 2013
- Manuscript Received: 6 DEC 2012
- American Pediatric Society/Society of Pediatric Research Student Research Program
- Children's Heart Foundation and the Research Institute at Nationwide Children's Hospital
- hypoplastic left heart syndrome;
- atrioventricular septal defect
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 Nkx2.5. 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.1702C>T variant in FOXP1 that predicted a potentially deleterious substitution of a highly conserved proline (p.Pro568Ser). This variant was not found in 287 controls but is present in dbSNP at a 0.2% frequency. The orthologous murine Foxp1 p.Pro596Ser mutant protein displayed deficits in luciferase reporter assays and resulted in increased proliferation and Nkx2.5 expression in cardiomyoblasts. Our data suggest that haploinsufficiency of FOXP1 is associated with human CHD.