Pos0983 tet2 mosaicism in human is associated with a complex phenotype including lymphoproliferation, autoimmunity, immunodeficiency, and hematologic malignancy

Background The TET2 gene encodes ten-eleven translocation methylcytosine dioxygenase 2 (TET2). TET2 is an epigenetic regulator that converts 5-methlycytosine to 5-hydroxymethylcytosine and also interacts with histone-modifying enzymes and transcription factors. Somatic mutations in TET2 are early events in clonal expansion and are found in association with myeloid and lymphoid haematological diseases. Germline mutations in TET2 have only been described in 3 children of consanguineous parents. These mutations led to immunodeficiency and lymphoma and early mortality in childhood. Objectives To assess the clinical and immunological consequences of a combination of a germline and a somatic mutation in TET2 . Methods Genetic analysis was done by whole exome sequencing. An in-depth immunological analysis was performed. Results Clinical phenotype: The patient of non-consanguineous parents presented at the age of 38 with axial spondyloarthritis. Apart from trace homogeneous fluorescence on the HEp2 cell his immunologic work-up was unremarkable. After start of a TNF-inhibitor he developed persisting fever, serositis, interstitial lung disease, peripheral arthritis and a pronounced lymphadenopathy/splenomegaly. His condition improved after the TNF-inhibitor was changed to an IL-17-inhibitor combined with prednisone (up to 40 mg/d), but lymphadenopathy persisted and the patient recurrently suffered from fevers, fatigue and pleurisy. Lymphnode biopsies showed no signs of malignancy. The patient had recurrent episodes of pancytopenia that spontaneously improved and he developed two episodes of pneumonia. Furthermore, he suffered from recurrent episodes of herpes zoster. Immunological results On immunologic work-up the patient had a polyclonal hypergammaglobulinemia and autoantibody testing revealed a homogenous ANA (1:1600), and positive anti-nucleosomen-, anti-PM-Scl75-, anti-SRP-, anti-PL-12-, anti-phospholipid-, anti-dsDNA- and anti-MPO-autoantibodies. Despite of increased amounts of immunoglobulins the patient developed a progressive and persistent loss of B cells (Figure 1), with an increased expression of CD80/86 on the remaining memory B cells. Within the T cell compartment double-negative T cells were increased. Results of whole exome sequencing Whole exome sequencing revealed a germline mutation in TET2 with the variant c3641G>A; pArg1214Gln in the heterozygous state (NAF 0.53; NM_001127208.3). This mutation affects a phylogenetically conserved amino acid and is classified as predominantly pathogenic in the in silico prediction. Another variant identified is the mutation c.1864C>T; p.Gln622, which leads to the emergence of a stop codon (NAF 0.41). This variant was only detectable as a low-grade mosaic (5-10%) in the buccal mucosa in the control, possibly as a result of lymphocytic infiltration into the buccal mucosa. In leukocytes, this mutation was detectable in 83% of cells in the heterozygous state. Both mutations have a low frequency in the population (1-2/125000-150000; gnomAD). Hematogical malignancy 5 years after the progessive loss of B cells had started, the patient was diagnosed with a follicular B cell lymphoma and shortly after with AML with myelodysplasia-associated changes (AML-MRC). A familial-allogeneic peripheral blood stem cell transplantation was performed. During the now 6 months follow-up no relapse occurred. Conclusion Combined heterozygous germline and somatic mutations in TET2 are associated with a very complex phenotype combining autoimmunity, lymphoproliferation and hematological malignancy, may present in adulthood and thus clinically differ from combined heterozygous germline mutations with early onset in childhood. References [1]Stremenova Spegarova J et al; Germline TET2 loss of function causes childhood immunodeficiency and lymphoma. Blood. 2020 Aug 27;136(9):1055-1066 [2]Zhang et al; Human TET2 bridges cancer and immunity. Blood. 2020 Aug, 27;136(9):1018-1019. doi: 10.1182/blood.2020006881. Figure 1. Acknowledgements: NIL. Disclosure of Interests None Declared.