Alagille syndrome is a multi-system disorder characterized by highly variable expressivity, most frequently caused by heterozygous JAG1 gene variants.  Classic diagnostic criteria combine the presence of bile duct paucity on liver biopsy with three of five systems affected (liver, heart, skeleton, eye and dysmorphic facies). However, up to one-third of patients presenting with only one or two clinical features of Alagille syndrome will have a disease-causing variant in the JAG1 gene  (Guegan et al. 2011: Clin Gen Jul).  Between 50-60% of cases result from a de novo variant. If the familial JAG1 variant is not detected in the leucocyte DNA of either of the probands parents, siblings of the proband are at low, but slightly increased risk due to germline mosaicism.

Disease-causing variants in the NOTCH2 gene have been reported in 2/11 (18%) probands and 3 of their affected relatives, who did not have a disease-causing variant detected in the JAG1 gene. Renal manifestations were present in all the affected individuals (McDaniell et al. 2006: Am J Hum Genet 79(1):169-173).

Variants in exon 34 of the NOTCH2 gene are also associated with Hajdu-Cheney syndrome.

The laboratory participates in the European Molecular Genetics Quality Network (EMQN) sequencing scheme.