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Germline TET2 loss of function causes childhood immunodeficiency and lymphoma.

Stremenova Spegarova, Jarmila and Lawless, Dylan and Mohamad, Siti Mardhiana Binti and Engelhardt, Karin R. and Doody, Gina and Shrimpton, Jennifer and Rensing-Ehl, Anne and Ehl, Stephan and Rieux-Laucat, Frederic and Cargo, Catherine and Griffin, Helen and Mikulasova, Aneta and Acres, Meghan and Morgan, Neil V. and Poulter, James A. and Sheridan, Eamonn G. and Chetcuti, Philip and O'Riordan, Sean and Anwar, Rashida and Carter, Clive R. and Przyborski, Stefan and Windebank, Kevin and Cant, Andrew J. and Lako, Majlinda and Bacon, Chris M. and Savic, Sinisa and Hambleton, Sophie (2020) 'Germline TET2 loss of function causes childhood immunodeficiency and lymphoma.', Blood., 136 (9). pp. 1055-1066.


Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.

Item Type:Article
Full text:Publisher-imposed embargo
(AM) Accepted Manuscript
File format - PDF
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Date accepted:No date available
Date deposited:10 September 2020
Date of first online publication:27 August 2020
Date first made open access:No date available

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