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Alagille syndrome is a multisystem genetic disorder that can affect the liver, heart, skeleton, eyes, face, kidneys, and blood vessels, with a wide range of severity. Some family members carrying the same genetic change have only mild, barely noticeable features, while others develop serious, even life-threatening complications. The condition is caused by changes, known as pathogenic variants, in one of two genes that both take part in a cell communication pathway called the Notch signaling pathway, which guides how the bile ducts, heart, and other organs form correctly before and after birth. In both genes, the disorder arises because one of the two copies a person carries is not working properly, a mechanism called haploinsufficiency, meaning a single working copy is not enough on its own to guide normal organ development.
• JAG1, located on chromosome 20, accounts for approximately ninety-four percent of cases. It provides instructions for a protein called Jagged-1, which signals to Notch receptors on neighboring cells during development. Most JAG1 changes are loss-of-function changes, in which the protein is not made at all or cannot function once made.
• NOTCH2, located on chromosome 1, accounts for approximately two and a half percent of cases. It provides instructions for one of the receptor proteins that Jagged-1 binds to. NOTCH2 changes are more often changes that alter a single building block of the protein rather than eliminating it entirely.A small proportion of people who show clear features of Alagille syndrome do not have an identifiable change in either gene on current testing, which suggests that other, not-yet-identified genes or mechanisms may occasionally be involved and that testing technology continues to evolve.
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