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Germline TET2 loss of function causes childhood immunodeficiency and lymphoma

Stremenova Spegarova, Jarmila; Lawless, Dylan; Mohamad, Siti Mardhiana Binti; Engelhardt, Karin R.; Doody, Gina; Shrimpton, Jennifer; Rensing-Ehl, Anne; Ehl, Stephan; Rieux-Laucat, Frederic; Cargo, Catherine; Griffin, Helen; Mikulasova, Aneta; Acres, Meghan; Morgan, Neil V.; Poulter, James A.; Sheridan, Eamonn G.; Chetcuti, Philip; O'Riordan, Sean; Anwar, Rashida; Carter, Clive R.; Przyborski, Stefan; Windebank, Kevin; Cant, Andrew J.; Lako, Majlinda; Bacon, Chris M.; Savic, Sinisa; Hambleton, Sophie

Authors

Jarmila Stremenova Spegarova

Dylan Lawless

Siti Mardhiana Binti Mohamad

Karin R. Engelhardt

Gina Doody

Jennifer Shrimpton

Anne Rensing-Ehl

Stephan Ehl

Frederic Rieux-Laucat

Catherine Cargo

Helen Griffin

Aneta Mikulasova

Meghan Acres

Neil V. Morgan

James A. Poulter

Eamonn G. Sheridan

Philip Chetcuti

Sean O'Riordan

Rashida Anwar

Clive R. Carter

Kevin Windebank

Andrew J. Cant

Majlinda Lako

Chris M. Bacon

Sinisa Savic

Sophie Hambleton



Abstract

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.

Citation

Stremenova Spegarova, J., Lawless, D., Mohamad, S. M. B., Engelhardt, K. R., Doody, G., Shrimpton, J., …Hambleton, S. (2020). Germline TET2 loss of function causes childhood immunodeficiency and lymphoma. Blood, 136(9), 1055-1066. https://doi.org/10.1182/blood.2020005844

Journal Article Type Article
Online Publication Date Aug 27, 2020
Publication Date 2020-08
Deposit Date Sep 10, 2020
Journal Blood
Print ISSN 0006-4971
Electronic ISSN 1528-0020
Publisher American Society of Hematology
Peer Reviewed Peer Reviewed
Volume 136
Issue 9
Pages 1055-1066
DOI https://doi.org/10.1182/blood.2020005844


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