Genetics of Alagille syndrome

Alagille syndrome is a multi-system genetic disorder characterized by anomalies of the intrahepatic bile ducts, heart, skeleton, and eye, which are associated with characteristic facial features. The expressivity of the disorder is highly variable. Since the first descriptions of Alagille syndrome just over 30 years ago, appreciation of the clinical variability and complexity of this disorder has grown. Identification of Jagged1 (which codes for a ligand that functions in the Notch signaling pathway) as the disease-causing gene has led to the development of a molecular assay for carrier detection, which has revealed the wide spectrum of phenotypes associated with Jagged1 mutations. Liver (bile duct paucity and clinical cholestasis) and cardiac (pulmonic stenosis/atresia, and tetralogy of Fallot) findings account for the vast majority of morbidity and mortality in Alagille syndrome. Ocular and skeletal anomalies are frequently sub-clinical, and a smaller percentage of patients has more serious defects of the kidney or vasculature. Alagille syndrome-associated mutations in Jagged1 include total gene deletions, a variety of protein truncating mutations, splicing mutations, and missense mutations. All mutations known to date function by decreasing the available dosage of normal Jagged1, consistent with Alagille syndrome being caused by functional haploinsufficiency for Jagged1. Currently, Jagged1 mutations can be identified in about 90% of patients with a clinically defined diagnosis of Alagille syndrome. Mutations are de novo in approximately 60% of cases. There are multiple examples of individuals with apparently isolated cardiac disease who are carriers of a JAG1 mutation, consistent with the noted variable expressivity of JAG1 mutations. This review will summarize the clinical and molecular genetic findings on individuals with mutations in the Jagged1 gene.