Alagille syndrome (AGS) is an autosomal dominant disorder characterized by intrahepatic cholestasis, heart defects, abnormal vertebrae, and a distinctive facial appearance. The identification of cytogenetic deletions in rare AGS patients has allowed the gene to be mapped to 20p12. By generating a cloned contig of the critical region and using fluorescent in situ hybridization, the candidate region was narrowed to 250 kb. Within this region, the Jagged1 gene was identified, which encodes a ligand for the Notch receptor. Mutational analysis of DNA samples from non-deletion AGS patients revealed three frame-shift mutations, two splice donor mutations, and one mutation abolishing RNA expression from the altered allele. These findings suggest that AGS is caused by haploinsufficiency of JAG1. The role of Jagged1 as a Notch ligand adds significance to this observation, as Notch signaling is critical for cell fate determination in early development.Alagille syndrome (AGS) is an autosomal dominant disorder characterized by intrahepatic cholestasis, heart defects, abnormal vertebrae, and a distinctive facial appearance. The identification of cytogenetic deletions in rare AGS patients has allowed the gene to be mapped to 20p12. By generating a cloned contig of the critical region and using fluorescent in situ hybridization, the candidate region was narrowed to 250 kb. Within this region, the Jagged1 gene was identified, which encodes a ligand for the Notch receptor. Mutational analysis of DNA samples from non-deletion AGS patients revealed three frame-shift mutations, two splice donor mutations, and one mutation abolishing RNA expression from the altered allele. These findings suggest that AGS is caused by haploinsufficiency of JAG1. The role of Jagged1 as a Notch ligand adds significance to this observation, as Notch signaling is critical for cell fate determination in early development.