What genetic tests are recommended for confirming a diagnosis of Alagille Syndrome in a patient with suspected symptoms?

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 ¹. 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., 1993; Mitchell et al., 2018; Gilbert and 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 ¹ (Adam et al., 1993; Mitchell et al., 2018; Gilbert and Loomes, 2021).