Alagille syndrome is an autosomal dominant disorder with high penetrance but variable expressivity. Alagille syndrome 1 (ALGS1; MIM 118450) is caused by mutations in the JAG1 gene, encoding jagged-1, a ligand for the Notch receptors.  Alagille syndrome 2 (ALGS2; MIM 610205) is caused by mutations in NOTCH2, which encodes a transmembrane Notch receptor.  Interactions between Notch ligands and receptors regulate signaling pathways important for cell fate determination. The main clinical findings of Alagille syndrome include cholestasis due to bile duct paucity, congenital heart defects, skeletal abnormalities, a characteristic facial appearance, eye abnormalities, and renal disease. Cardiovascular findings include tetralogy of Fallot, peripheral pulmonary artery stenosis, atrial and/or ventricular septal defects, and coarctation of the aorta. Butterfly vertebra is the most common skeletal finding, particularly in individuals with JAG1 mutations.  Other findings include narrowing of interpeduncular spaces in the lumbar spine, spina bifida occulta, and short fingers and ulnae. Facial features consist of broad forehead, triangular face, prominent zygomatic arch and moderate hypertelorism. Posterior embryotoxon and retinal pigmentary changes are common ophthalmological findings.  Approximately 95% of patients with Alagille syndrome have a mutation in the JAG1 gene. About 2% of Alagille patients have a mutation in the NOTCH2 gene.

Mutations in the ATP8B1 gene cause autosomal recessive disorders: cholestasis, benign recurrent intrahepatic, 1 (BRIC1; MIM 243300) and cholestasis, progressive familial intrahepatic, 1 (PFIC1; MIM 211600). BRIC1 is characterized by intermittent episodes of cholestasis without extrahepatic bile duct obstruction. PFIC1 is characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood. Extrahepatic findings are not usually present. Recently, a patient with clinical findings consistent with ALGS (ALGS, ATP8B1 related) was found to have a compound heterozygous mutation in ATP8B1.

Copy number variation (CNV) analysis of the Alagille syndrome genes is also offered as a panel. Additionally, CTGT offers a comprehensive test (both NGS and CNV panels) for these genes. Panel genes are also offered as individual sequencing and deletion/duplication tests unless otherwise indicated.

The Alagille syndrome NGS panel consists of three genes: ATP8B1, JAG1 and NOTCH2.