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Magg, Thomas; Shcherbina, Anna; Arslan, Duran; Desai, Mukesh M.; Wall, Sarah; Mitsialis, Vanessa; Conca, Raffaele; Unal, Ekrem; Karacabey, Neslihan; Mukhina, Anna; Rodina, Yulia; Taur, Prasad D.; Illig, David; Marquardt, Benjamin; Hollizeck, Sebastian; Jeske, Tim; Gothe, Florian; Schober, Tilmann; Rohlfs, Meino; Koletzko, Sibylle; Lurz, Eberhard; Muise, Aleixo M.; Snapper, Scott B.; Hauck, Fabian; Klein, Christoph and Kotlarz, Daniel (2019): CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease. In: Inflammatory Bowel Diseases, Vol. 25, No. 11: pp. 1788-1795

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Background: Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes. Methods: To identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID. Results: Whole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency. Conclusion: Our study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.

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