An RTEL1 Mutation Links to Infantile-Onset Ulcerative Colitis and Severe Immunodeficiency
2Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center
3Sackler Faculty of Medicine, Tel Aviv University
4Division of Newborn Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh
5Department of Immunology, University of Pittsburgh
6Department of Developmental Biology, University of Pittsburgh
7Department of Genetics, The Silberman Institute of Life Science, The Hebrew University of Jerusalem
8Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital,
9Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital
10Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital
11Harvard Medical School, Harvard University
12Immunology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Center
13Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center
Purpose: More than 50 different monogenic disorders causing inflammatory bowel disease (IBD) have been identified. Our goal was to characterize the clinical phenotype, genetic workup, and immunologic alterations in an Ashkenazi Jewish patient that presented during infancy with ulcerative colitis and unique clinical manifestations.
Methods :Immune workup and whole-exome sequencing were performed, along with Sanger sequencing for confirmation. Next-generation sequencing of the TCRB and IgH was conducted for immune repertoire analysis. Telomere length was evaluated by in-gel hybridization assay. Mass cytometry was performed on patient’s peripheral blood mononuclear cells, and compared with control subjects and patients with UC.
Results: The patient presented in infancy with failure to thrive and dysmorphic features, consistent with a diagnosis of dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. Severe ulcerative colitis manifested in the first year of life and proceeded to the development of a primary immunodeficiency, presenting as Pneumocystis jiroveci pneumonia and hypogammaglobulinemia. Genetic studies identified a deleterious homozygous C.3791G>A missense mutation in the helicase regulator of telomere elongation 1 (RTEL1), leading to short telomeres in the index patient. Immune repertoire studies showed polyclonal T and B cell receptor distribution, while mass cytometry analysis demonstrated marked immunological alterations, including a predominance of naïve T cells, paucity of B cells, and a decrease in various innate immune subsets.
Conclusions: RTEL1 mutations are associated with significant alterations in immune landscape and can manifest with infantile-onset IBD. A high index of suspicion is required in Ashkenazi Jewish families where the carriage rate of the C.3791G>A variant is high.