Abstract 2133: Mutations In Alk2 Are Associated With Congenital Atrioventricular Valve-And Septal Defects
BACKGROUND. A congenital heart defect is the most common form of birth defect. To date, several genes have been implicated in human congenital heart defects as for example GATA4, NKX2.5, CRELD and NOTCH1. ALK2 is a receptor for the TGFβ superfamily ligands, BMP 2,4,6 and 7. Binding of ALK2 by its ligand results in activation of Smad transcriptional factors. Conditional deletion of ALK2 in mice results in severe defects in atrioventricular valve-, canal-and septal formation. In addition, ALK2 has been implicated in left-right patterning disturbances.
METHODS/RESULTS Through a candidate-gene-screen of 300 patients with an atrioventricular valve- and/or septal defect in CONCOR, 3 patients were identified with a the novo mutation in ALK2, which was not detected in 600 healthy controls. All index patients had a primium type atrial septal defect with a cleft mitral valve leaflet. In two patients there was no evidence for other congenital malformations or other dysmorphic features and the other patient had Down’s syndrome. One index patient demonstrated left-right patterning defects of her abdominal organs. DNA of all first degree relatives was collected and affected family members underwent an echocardiogram. Among affected first degree relatives only mild or no cardiac defects were observed. The figure shows a kindred of 4 generations of one family with an ALK2 mutation, demonstrating segregation of mutation with (cardiac) phenotype.
CONCLUSION Mutations in ALK2 are implicated in human congenital heart defects. Due to mild penetrance, other additive factors might play a role as for example epigenetic mechanisms, or a certain genetic background.