Genetic testing for confirming a diagnosis of Alagille syndrome primarily involves sequencing and deletion/duplication analysis of the JAG1 gene, which is mutated in the majority of cases. This test identifies pathogenic variants responsible for the syndrome's characteristic multisystem features, including liver, heart, skeletal, and eye abnormalities. In cases where JAG1 mutations are not detected, testing for NOTCH2 gene mutations is recommended, as these are less common but also causative of Alagille syndrome. Both genes are part of the Notch signaling pathway, critical in developmental processes.
This approach aligns with UK clinical practice guidelines that emphasize targeted genetic testing for JAG1 and NOTCH2 to confirm diagnosis in patients with suspected Alagille syndrome based on clinical features NICE CG71. Recent literature further supports this strategy, highlighting that comprehensive genetic analysis including sequencing and copy number variation assessment of these genes improves diagnostic yield Adam et al. 1993Mitchell et al. 2018Gilbert & Loomes 2021.
Therefore, the recommended genetic tests are:
- JAG1 gene sequencing and deletion/duplication analysis
- NOTCH2 gene sequencing if JAG1 testing is negative
This testing confirms the diagnosis, guides clinical management, and informs genetic counseling for affected families NICE CG71 Adam et al. 1993Mitchell et al. 2018Gilbert & Loomes 2021.
Key References
- CG71 - Familial hypercholesterolaemia: identification and management
- NG78 - Cystic fibrosis: diagnosis and management
- CG164 - Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer
- (Adam et al., 1993): Alagille Syndrome.
- (Mitchell et al., 2018): Alagille Syndrome.
- (Gilbert and Loomes, 2021): Alagille syndrome and non-syndromic paucity of the intrahepatic bile ducts.