Novel Germline TET2 Mutations in Two Unrelated Patients with Autoimmune Lymphoproliferative Syndrome-Like Phenotype and Hematologic Malignancy

Enrichment of Immune Dysregulation Disorders in Adult Patients with Human Inborn Errors of Immunity

“…Eleven patients (25%) with autoimmune lymphoproliferative syndrome (ALPS) due to germline and somatic FAS gene variants along with a germline FASL gene variant were the most common pathogenic finding [ 19 – 22 ]. We also detected four patients with germline variants in GATA2 gene (9.1%) and susceptibility to mycobacteria, myelodysplastic syndrome, acute myelogenous leukemia, chronic myelomonocytic leukemia, and/or lymphedema [ 23 ]; three patients (6.8%) with variants in CTLA4 gene and immune dysregulation; three patients (6.8%) with variants in TET2 gene and ALPS-like phenotype, one of these patients with the biallelic form and two with the monoallelic form of the disease [ 24 ]; two related patients (4.5%) with a congenital neutropenia due to an ELANE genetic defect; two unrelated patients with NFKB1 deficiency (4.5%) and common variable immunodeficiency (CVID) phenotype; two brothers (4.5%) were compound heterozygous for variants in PGM3 gene with very high IgE levels, immunodeficiency, and severe atopy; two unrelated patients (4.5%) with the autosomal dominant (AD) form of activated phosphoinositide 3-kinase syndrome type 2 (APDS2) [ 25 ] characterized by severe bacterial infections, reduced memory B cells, and increased transitional B cells, lymphadenopathy/splenomegaly and lymphoproliferation/lymphoma; two brothers with a Griscelli syndrome type 2 due to a RAB27A molecular defect (4.5%) with neurological symptoms without albinism and decreased NK cytotoxicity and degranulation; two unrelated patients with Job syndrome and hyper IgE due to STAT3 AD loss of function (LOF) variants (4.5%); two unrelated patients (4.5%) with a Di George syndrome due to del22q11.2 and immune dysregulation. Finally, single patients were also diagnosed with ADA2, BTK, C8B, CD8A, LIG4, MAGT1, TACI, TAP1, and TLR7 deficiencies.…”

“…2 E). Only the patient with the biallelic form of TET2 died after HSCT [ 24 ]. Although HSCT is considered the main therapeutic and curative approach for children with IEI, it has been relatively unusual among IEI-adults due to difficulties related to the selection of adequate candidates and donors, optimal timing, conditioning regimens, and specific management after transplantation.…”

TET2 and clonal hematopoiesis-related gene variants in patients with acquired pure red cell aplasia

“…Although somatic TET2 variants are frequently associated with myeloid malignancies [16][17][18][19][20], T-cell lymphoma [21,22], and CHIP [23], germline TET2 variants have also been reported in various diseases, although rare, including myeloid malignancies [13][14][15], lymphoid malignancies [24], immune dysregulation syndromes [25,26], and pulmonary arterial hypertension [27,28]. Loss of function variants of TET2 lead to DNA hypermethylation, which can cause enhanced in ammation [27] or immune dysregulation [24][25][26]. López et al reported that heterozygous TET2 lossof-function variants could induce increased methylation in CD8 + cells.…”

“…Five of these variants had a VAF ≥ 40%, 3 cases were con rmed as germline variants, and 1 patient with the N813S variant was also a member of a family with N813S germline variants. Although somatic TET2 variants are frequently associated with myeloid malignancies [16][17][18][19][20], T-cell lymphoma [21,22], and CHIP [23], germline TET2 variants have also been reported in various diseases, although rare, including myeloid malignancies [13][14][15], lymphoid malignancies [24], immune dysregulation syndromes [25,26], and pulmonary arterial hypertension [27,28]. Loss of function variants of TET2 lead to DNA hypermethylation, which can cause enhanced in ammation [27] or immune dysregulation [24][25][26].…”