Genetics of Alagille Syndrome

  • Melissa A. Gilbert
  • Nancy B. SpinnerEmail author


Alagille syndrome is a rare, autosomal dominant disorder that is caused by mutations in JAG1 or NOTCH2, two genes that are integral components of Notch signaling. Clinical diagnostics is currently able to identify roughly 96% of mutations in patients through a combination of gene sequencing (JAG1 and NOTCH2) and deletion/duplication analysis (JAG1). The disease shows variable expressivity, and functional studies have not been able to establish any link between type or location of mutation and corresponding phenotype. The high number of reported loss-of-function variants, as well as data on a limited selection of missense mutations that show inappropriate protein folding, trafficking, or function, suggests that Alagille syndrome is due to gene haploinsufficiency. Ongoing research efforts in the genetics of Alagille syndrome are currently focused on identifying causes for the observed variable expressivity. A hypothesis in the field is that another gene may function to modify features of the disease, and a growing number of candidate gene modifiers have now been proposed. We hope that further understanding of both the variable expressivity of this disease and the molecular function of reported missense mutations will drive therapeutics to treat the more severe features of this disease.


JAG1 NOTCH2 Notch signaling Haploinsufficiency Variable expressivity 


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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PathologyThe Children’s Hospital of Philadelphia and the Perelman School of Medicine at The University of PennsylvaniaPhiladelphiaUSA

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