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Germline TET2 loss-of-function causes childhood immunodeficiency and lymphoma

Lookup NU author(s): Dr Jarmila SpegarovaORCiD, Dr Karin Engelhardt, Dr Helen GriffinORCiD, Dr Aneta Mikulasova, Dr Meghan Acres, Dr Kevin Windebank, Professor Andrew Cant, Professor Majlinda LakoORCiD, Dr Christopher Bacon, Professor Sophie HambletonORCiD



Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied three children with an immunodysregulatory syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity and lymphoma of either B- (n=2) or T-cell (n=1) origin. All three 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 either 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 2/3 patients. Moreover, TET2 deficient B-cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced-pluripotent stem cells was skewed towards 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.

Publication metadata

Author(s): Spegarova JS, Lawless D, Mohamad SMB, Engelhardt KR, Doody G, Shrimpton J, Rensing-Ehl A, Ehl S, Rieux-Laucat F, Cargo C, Griffin H, Mikulasova A, Acres M, Morgan NV, Poulter JA, Sheridan EG, Chetcuti P, O'Riordan S, Anwar R, Carter C, Przyborski S, Windebank K, Cant AJ, Lako M, Bacon CM, Savic S, Hambleton S

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2020

Volume: 136

Issue: 9

Pages: 1055-1066

Print publication date: 27/08/2020

Online publication date: 09/06/2020

Acceptance date: 28/04/2020

Date deposited: 02/07/2020

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology


DOI: 10.1182/blood.2020005844

PubMed id: 32518946


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Funder referenceFunder name
09005Bloodwise (Formerly Leukaemia and Lymphoma Research)
207556/Z/17/ZWellcome Trust