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Genetics of Alagille Syndrome

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Alagille Syndrome

Abstract

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.

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Authors and Affiliations

  1. Department of Pathology, The Children’s Hospital of Philadelphia and the Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA

    Melissa A. Gilbert & Nancy B. Spinner

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  1. Melissa A. Gilbert
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  2. Nancy B. Spinner
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Correspondence to Nancy B. Spinner .

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  1. Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada

    Binita M. Kamath

  2. Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Kathleen M. Loomes

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Gilbert, M.A., Spinner, N.B. (2018). Genetics of Alagille Syndrome. In: Kamath, B., Loomes, K. (eds) Alagille Syndrome. Springer, Cham. https://doi.org/10.1007/978-3-319-94571-2_3

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