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An RTEL1 Mutation Links to Infantile-Onset Ulcerative Colitis and Severe Immunodeficiency

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Abstract

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.

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Acknowledgments

We would like to thank the patients and their families for participating in this study. We appreciate the support by the German Academic Exchange Service DAAD (CK, SS, and RS) as well as the Care-for-Rare Foundation.

Authorship Contribution

AZ, TS, BW, RS, and DSS contributed to sample acquisition. AZ, LW, LK, AA, TJ, MH, VM, SW, DK CK, SBS, YT, RS, and DSS contributed to data analysis. DSS designed the study, coordinated research studies, and wrote the manuscript.

Funding

DSS, SBS, and CK are supported by the Leona M. and Harry B. Helmsley Charitable Trust. SBS is also supported by the Wolpow Chair in IBD Research and Treatment and the Translational Research Program (Boston Children’s Hospital).

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Authors and Affiliations

  1. Pediatric Department A, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel

    Alma Ziv, Tali Stauber & Raz Somech

  2. Pediatric Gastroenterology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel

    Alma Ziv, Lael Werner, Batia Weiss & Dror S. Shouval

  3. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Alma Ziv, Lael Werner, Tali Stauber, Batia Weiss, Raz Somech & Dror S. Shouval

  4. Division of Newborn Medicine, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

    Liza Konnikova

  5. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA

    Liza Konnikova

  6. Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA

    Liza Konnikova

  7. Department of Genetics, The Silberman Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem, Israel

    Aya Awad & Yehuda Tzfati

  8. Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany

    Tim Jeske, Maximilian Hastreiter, Daniel Kotlarz & Christoph Klein

  9. Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, MA, USA

    Vanessa Mitsialis, Sarah Wall & Scott B Snapper

  10. Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, Boston, MA, USA

    Vanessa Mitsialis & Scott B Snapper

  11. Harvard Medical School, Boston, MA, USA

    Vanessa Mitsialis & Scott B Snapper

  12. Immunology Service, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel

    Tali Stauber & Raz Somech

  13. Jeffrey Modell Foundation Center, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel

    Tali Stauber & Raz Somech

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  1. Alma Ziv
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  2. Lael Werner
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  3. Liza Konnikova
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  13. Yehuda Tzfati
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  16. Dror S. Shouval
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Corresponding author

Correspondence to Dror S. Shouval.

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The study was approved by the local IRB committee at Sheba Medical Center. Informed written consent was obtained from the parents.

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The authors declare that they have no conflict of interest.

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Ziv, A., Werner, L., Konnikova, L. et al. An RTEL1 Mutation Links to Infantile-Onset Ulcerative Colitis and Severe Immunodeficiency. J Clin Immunol 40, 1010–1019 (2020). https://doi.org/10.1007/s10875-020-00829-z

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