Clinical and molecular genetics of Alagille syndrome.

Alagille syndrome (AGS) is a dominantly inherited disorder characterized by bile duct paucity and resultant liver disease in combination with cardiac, skeletal, ocular, and facial abnormalities. Jagged1 (JAG1) has been identified as the AGS disease gene. It encodes a ligand in the Notch signaling pathway that is involved in cell fate determination. AGS is the first developmental disorder to be associated with this pathway. It shows highly variable expressivity, and diagnosis in mildly affected persons can be difficult without molecular analysis. Currently, JAG1 mutations are detected in about 70% of patients with AGS and include total gene deletions as well as protein truncating, splicing, and missense mutations. Mutations are located across the gene within the evolutionarily conserved motifs of the protein. There is no phenotypic difference between patients with deletion of the entire JAG1 gene and those with intragenic mutations. This suggests that haploinsufficiency for JAG1 is a mechanism causing AGS.