EGAGenomicsIllumina HiSeq 2500, Illumina HiSeq 4000, ILLUMINAOtherhttps://ega-archive.org/studies/EGAS00001002765EGAEGA study EGAS00001002765SPTCL exome dataEGArestrictedcluster, T-cell membrane protein 3, Thymus-Dependent Lymphocytes, Panniculitis, syndrome associated with disease or disorder, TIMD-3, subcutaneous, Timd3, T-cell immunoglobulin and mucin domain-containing protein 3, T-Lymphocyte, Germinoblastoma, Clusters, Panniculitides, Malignant, Germinoblastic Sarcoma, Tim3, TIM3, syndromic disease or disorder, Cell, Mutations, T-cell immunoglobulin mucin receptor 3, Malignant Lymphomas, Cold, TIMD3, Reticulolymphosarcomas, symptom cluster, "syndrome, T Lymphocyte, T-Cell, Symptom Cluster, "syndrome" EXACT [MTH:NOCODE], symptom clusters, panniculitis, symptom, Germinoblastic Sarcomas, inflammation of subcutaneous adipose tissue, Germinoblastic, immature T cell, Lymphomas, T lymphocyte, Reticulolymphosarcoma, Sarcomas, T-cell, Subacute Nodular Migratory, HAVcr-2, Cold Panniculitides, T-Cells, Thymus-Dependent, T, Lymphocytes, syndrome, subcutaneous adipose tissue inflammation, T-lymphocyte, Germinoblastomas, syndromes, Subcutaneous adipose tissue, TIM-3, Subcutaneous tissue, Symptom, Thymus-Dependent Lymphocyte, clusters, T Cells, Malignant Lymphoma, Sarcoma, T cell, NOS" EXACT [SNOMEDCT_2005_07_31:64572001], Syndromes, subcutis, Cluster, Cold Panniculitis, syndromic disease, mature T cell, Lymphoma, Cells, Symptom Clusters, T Cell, T Lymphocytes, Thymus Dependent Lymphocytes, Lymphocyte, symptom.Nonhodgkin, SUBCUTANEOUS PANNICULITIS-LIKE, Globulin, familial erythrophagocytic lymphohistiocytosis, Germinoblastoma, Nonhodgkin's Lymphoma, Mutations, Small, T-cell immunoglobulin mucin receptor 3, protein polypeptide chains, Reticulosarcoma, T-CELL LYMPHOMA, symptoms, 1, Lymphomas, East, "Hemophagocytic syndrome" EXACT [NCI2004_11_17:C35439], Fresh Frozen, Undifferentiated, Reticulum Cell, T-Cells, CG12919, Tissue, T, subcutaneous adipose tissue inflammation, Familial, proteins, Hemophagocytic Histiocytoses, DIF, High-Grade Lymphoma, Infection-Associated, Mixed Lymphocytic-Histiocytic, TNFSF2, Reticulosarcomas, Familial Hemophagocytic Histiocytoses, TIM, Tim, Thymus Dependent Lymphocytes, plasma, dif, screening, tnfa, T-cell membrane protein 3, TIMD-3., haemophagocytic syndrome, Noncleaved-Cell Lymphoma, familial, TNFA, integral to membrane, Mixed Lymphocytic-Histiocytic Lymphoma, Mucin 3, tim, Far East, "Haemophagocytic lymphohistiocytosis" EXACT [SNOMEDCT_2005_07_31:190958003], Lymphohistiocytosis, Ritsu, Regg1, TPID, Reactive Hemophagocytic Syndrome, Non-Hodgkin's Lymphoma, activation, East Asian Peoples, hemophagocytic disorder, Diffuse Lymphoma, portion of blood plasma, Lymphatic Sarcoma, signs, Familial Hemophagocytic, T-lymphocyte, Germinoblastomas, Hemophagocytic Histiocytosis, TIM-3, Reticulum-Cell Sarcoma, blood plasm, T cell, Infection-Associated Hemophagocytic Syndrome, People, subcutis, Chromosome, Lymphoma, Cells, Tnfa, T Cell, Globulins, SPTCL, "Hemophagocytic syndrome (disorder)" EXACT [SNOMEDCT_2005_07_31:127069007], Familial Hemophagocytic Histiocytosis, Fresh, Pleomorphic Lymphomas, Lymphocytic-Histiocytic Lymphoma, familial histiocytic reticulosis, lifespan, Fresh Frozen Plasma, Immunoglobulin, TNF, Intermediate-Grade, Erythrophagocytic Lymphohistiocytoses, High-Grade Lymphomas, Diffuse Undifferentiated, protein-containing complex, rit, Pleomorphic Lymphoma, Diffuse Lymphomas, Undifferentiated Lymphomas, High-Grade, Intermediate Grade, Reticulosis, Gene Products, CG3234, panniculitis, Diffuse Mixed-Cell Lymphomas, Lymphohistiocytoses, Low-Grade, Hemophagocytic Reticuloses, Asian People, Sarcomas, Diffuse Mixed-Cell Lymphoma, Hemophagocytic Lymphohistiocytosis, TPI, Tissues, RATTNF, Mixed-Cell Lymphomas, Reticulum Cell Sarcoma, Undifferentiated Lymphoma, DmelCG12919, Subcutaneous tissue, Small Noncleaved-Cell Lymphomas, Far East Asian, Diffuse, darth, Histiocytosis, mature T cell, familial hemophagocytic lymphohistiocytosis, Hymphohistiocytosis, Diffuse Mixed-Cell, constitutitional genetic, "Hemophagocytic Lymphohistiocytosis" EXACT [NCI2004_11_17:C34792], Familial Erythrophagocytic Lymphohistiocytoses, DmelCG3234, findings, Low-Grade Lymphoma, Erythrophagocytic Lymphohistiocytosis, xtnf, Intermediate-Grade Lymphoma, Proteins, Diffuse Undifferentiated Lymphomas, Primary, function, Mixed Lymphocytic-Histiocytic Lymphomas, East Asian, dtim, Cell, dt1, Frozen Plasmas, Hemophagocytic Lymphohistiocytosis Familial 1, prophase chromosome, Mixed Lymphocytic Histiocytic, Cytokine, Mixed Lymphoma, native protein, Diffuse Small Cleaved Cell Lymphoma, Non Hodgkins, Hemophagocytic Reticulosis, Germinoblastic Sarcomas, Immunomodulatory Therapy, Mixed Cell, Small Noncleaved-Cell, supply and distribution, dTIM, dTim, Hemophagocytic Lymphohistiocytoses, interphase chromosome, increased number, NHL, Small Cleaved Cell, Familial Erythrophagocytic, Histiocytoses, Gene Proteins, East Asians, Far East Asians, Cold Panniculitis, hereditary, Non-Hodgkin's, Small Cleaved-Cell Lymphoma, Familial Hemophagocytic Lymphohistiocytosis, TIMD-3, supply, Familial Histiocytic, Blood, Immune Globulin, Mixed Small and Large Cell Lymphoma, Hemophagocytic Syndromes, Timd3, T-cell immunoglobulin and mucin domain-containing protein 3, T-Lymphocyte, protein, Small Cleaved-Cell, Malignant Lymphomas, Membrane Tissues, TIMD3, Diffuse Mixed Small and Large Cell Lymphoma, T Lymphocyte, Lymphatic, Non-Hodgkin Lymphoma, Lymphatic Sarcomas, Familial Hemophagocytic Lymphocytosis, GEF5, Mixed Lymphomas, inflammation of subcutaneous adipose tissue, Mixed-Cell Lymphoma, protein aggregate, immature T cell, Eastern, xtnf-alpha, "Hemophagocytic lymphohistiocytosis (disorder)" EXACT [SNOMEDCT_2005_07_31:234437005], Reticulolymphosarcoma, Mixed Small and Large Cell, Lymphocytic-Histiocytic Lymphomas, Fresh Frozen Plasmas, increased, Non Hodgkin's Lymphoma, Eastern Asian Peoples, Subacute Nodular Migratory, regg1, Hemophagocytic Lymphocytosis, entire life cycle, Triose-phosphate isomerase, membrane region, Mucin 3B, Mucin 3A, non-Hodgkin's lymphoma, Familial Histiocytic Reticulosis, chromatid, Primary Hemophagocytic Hymphohistiocytosis, Atypical Diffuse Small Lymphoid, genetic, T Cells, Malignant Lymphoma, Sarcoma, Diffuse Small Cleaved-Cell Lymphoma, Immune, Immunomodulations, Primary Hemophagocytic Lymphohistiocytoses, Therapies, Hemophagocytic, subcutaneous panniculitis-like T-cell lymphoma, Low-Grade Lymphomas, Small Non Cleaved Cell, Therapy, Membrane Tissue, Frozen Plasma, Familial Hemophagocytic Lymphohistiocytoses, C77407, Alpha/Beta type, membranous organ component, Plasmas, Tim3, TIM3, TIM1, Nonhodgkins, Reticulolymphosarcomas, T-Cell, Reticuloses, tim1, tnf-alpha, Non-Hodgkin lymphoma, Germinoblastic, Nonhodgkins Lymphoma, Reticulum-Cell Sarcomas, Non Hodgkin, T-cell, Primary Hemophagocytic Hymphohistiocytoses, membrane of organ, HAVcr-2, Hemophagocytic Lymphocytoses, non-Hodgkin lymphoma, life, Thymus-Dependent, Small Noncleaved Cell Lymphoma, Familial Hemophagocytic Lymphocytoses, TNFalpha, BcDNA:RH51659, Non-Hodgkin, Immunomodulatory Therapies, Subcutaneous adipose tissue, Lymphosarcoma, Thymus-Dependent Lymphocyte, immunoglobulin, subcutaneous panniculitis-like T-cell lymphoma (Alpha/Beta type), Patient, Eastern Asians, Non-Hodgkins Lymphoma, Primary Hemophagocytic Lymphohistiocytosis, inherited genetic, Hymphohistiocytoses, Small Non-Cleaved-Cell, Familial Erythrophagocytic Lymphohistiocytosis, accessory, TNF-alpha, Thymus-Dependent Lymphocytes, Small Non-Cleaved-Cell Lymphomas, P60, Asian, Gene, Malignant, Germinoblastic Sarcoma, Immunomodulatory, supernumerary, hTIM, Hemophagocytic Hymphohistiocytosis, antibody, Cold, TNF-a, Non-Hodgkins, polypeptide chain, Small Cleaved Cell Lymphoma, integral component of membrane, subcutaneous panniculitic T-cell lymphoma, Reactive, Lymphocytosis, Histiocytic Reticuloses, Blood Plasma, High Grade, entire lifespan, distribution, Primary Hemophagocytic, Eastern Asian People, Mixed Cell Lymphoma, Ect1, Nonhodgkin's, Clients, Blood Plasmas, Familial Hemophagocytic Reticuloses, region of membrane, Debt69, T Lymphocytes, Low Grade, Lymphocyte, Mucin-3B, membrane, Reticulum Cell Sarcomas, Mucin-3A, Panniculitis, Small Noncleaved-Cell Lymphoma, protein complex, 5.3.1.1, Non Hodgkin's, Diffuse Mixed Cell Lymphoma, ggr, Small and Large Cleaved-Cell, Panniculitides, Immune Globulins, Client, Pleomorphic, tnfsf2, natural protein, non-Hodgkins lymphoma, Lymphosarcomas, Reticulum-Cell, Protein, whole membrane, Lymphocytoses, Small Non Cleaved Cell Lymphoma, Mixed, T lymphocyte, Hemophagocytic Syndrome, Hemophagocytic Hymphohistiocytoses, Histiocytic Reticulosis, opsonin activity, Plasma, transmembrane, Cold Panniculitides, Diffuse Undifferentiated Lymphoma, Familial Histiocytic Reticuloses, FHL, Hemophagocytic Lymphohistiocytosis Familial -1, mel_tim, portion of plasma, Lymphocytes, Non-Cleaved-Cell Lymphoma, Membrane, Protein Gene Products, Familial Hemophagocytic Reticulosis, present in greater numbers in organism, non-Hodgkin's lymphoma (NHL), Small Noncleaved Cell, Intermediate-Grade Lymphomas, HEL-S-49, B cell receptor activity, Egr, Eastern Asian, Non Hodgkin Lymphoma, Small Non-Cleaved-Cell Lymphoma, Tnfsf1a, Mixed-Cell, Infection AssociatedfalseGermline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T-cell lymphomas with hemophagocytic lymphohistiocytic syndromeSub-cutaneous panniculitis-like T-cell lymphomas (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation which adversely impacts survival1,2. T-cell-immunoglobulin mucin-3 (TIM-3) is a modulator of immune responses expressed on subgroups of T- and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants in highly conserved residues of TIM-3, c.245A>G(p.Y82C) and c.291A>G(p.I97M), each with specific geographic distribution. Y82C-TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while I97M-TIM-3 occurs in Caucasians. Both variants induce protein misfolding and abrogate TIM-3’s plasma-membrane expression leading to persistent immune activation, increased production of inflammatory cytokines, including TNF-α and IL-1β, promoting HLH and SPTCL. Our findings highlight HLH/SPTCL as a new genetic entity and showcase TIM-3 mutations as the first causative genetic defect in SPTCL. While TIM-3-mutant HLH/SPTCL benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.2018-08-25 17:50:58EGAS000010027659606EGAD00001004310EGAC00001000992