Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis

Michael E. Horesh, Marta Martin-Fernandez, Conor Gruber, Sofija Buta, Tom Le Voyer, Eve Puzenat, Harry Lesmana, Yiming Wu, Ashley Richardson, David Stein, Stephanie Hodeib, Mariam Youssef, Jacob A. Kurowski, Elizabeth Feuille, Luis A. Pedroza, Ramsay L. Fuleihan, Alexandria Haseley, Alain Hovnanian, Pierre Quartier, Jérémie RosainGeorgina Davis, Daniel Mullan, O'Jay Stewart, Roosheel Patel, Angelica E. Lee, Rebecca Rubinstein, Leyla Ewald, Nikhil Maheshwari, Virginia Rahming, Ivan K. Chinn, James R. Lupski, Jordan S. Orange, Vanessa Sancho-Shimizu, Jean Laurent Casanova, Noura S. Abul-Husn, Yuval Itan, Joshua D. Milner, Jacinta Bustamante, Dusan Bogunovic

Research output: Contribution to journalArticlepeer-review


Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement. These findings suggest that individually rare JAK1 GoF variants may underlie an emerging syndrome with more common presentations of autoimmune and inflammatory disease (JAACD syndrome). More broadly, individuals who present with such conditions may benefit from genetic testing for the presence of JAK1 GoF variants.

Original languageEnglish
JournalJournal of Experimental Medicine
Issue number6
StatePublished - 3 Jun 2024


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