Germline TET2 loss of function causes childhood immunodeficiency and lymphoma

• Published in: Blood Vol. 136; no. 9; pp. 1055 - 1066
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.08.2020
• Subjects: Allografts; Apoptosis; B-Lymphocyte Subsets - pathology; Cellular Reprogramming Techniques; Codon, Nonsense; DNA Methylation; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Fatal Outcome; Female; Germ-Line Mutation; Hematopoietic Stem Cell Transplantation; Humans; Induced Pluripotent Stem Cells - pathology; Infant, Newborn; Loss of Function Mutation; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - pathology; Lymphoma, T-Cell, Peripheral - genetics; Lymphoma, T-Cell, Peripheral - pathology; Lymphoproliferative Disorders - genetics; Male; Mutation, Missense; Neoplasms, Multiple Primary - genetics; Pedigree; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; Severe Combined Immunodeficiency - genetics; Severe Combined Immunodeficiency - pathology; T-Lymphocyte Subsets - pathology; Whole Exome Sequencing
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2020005844

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. •We report autosomal-recessive germline deficiency of the methylcytosine dioxygenase TET2 in 3 immunodeficient children.•Their phenotype of immunodeficiency, autoimmunity and lymphoproliferation highlights requisite roles for TET2 in the human immune system. [Display omitted]