Germline TET2 loss of function causes childhood immunodeficiency and lymphoma

Jarmila Stremenova Spegarova, Dylan Lawless, Siti M B Mohamad, Karin R Engelhardt, Gina M Doody, Jennifer Shrimpton, Anne Rensing-Ehl, Stephan Ehl, Frédéric Rieux-Laucat, Catherine Cargo, Helen Griffin, Aneta Mikulasova, Meghan Acres, Neil Morgan, James Poulter, Eamonn Sheridan, Phillip Chetcuti, Sean O'Riordan, Rashida Anwar, Clive CarterStefan Przyborski, Kevin Windebank, Andrew Cant, Majlinda Lako, Chris Bacon, Sinisa Savic, Sophie Hambleton

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)
283 Downloads (Pure)


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.
Original languageEnglish
Pages (from-to)1055-1066
Number of pages12
Issue number9
Early online date9 Jun 2020
Publication statusPublished - 27 Aug 2020

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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