Treatment of Germline TET2 Deficiency with a Hypomethylating Agent

Clinical Presentation Patients with germline TET2 loss of function exhibit a syndrome of immunodeficiency, autoimmune lymphoproliferation, developmental delay, and predisposition to lymphoma. An 8-week-old infant was admitted with failure to thrive, ascites, respiratory failure, hepatosplenomegaly, lymphadenopathy, cytopenias, hypogammaglobulinemia, hypoalbuminemia, and nephrotic syndrome. The patient had chronic CMV and recurrent rhinovirus infections with secondary bacterial pneumonia requiring mechanical ventilation. Whole-genome sequencing revealed homozygous nonsense variants in TET2 (c.3075del p.(Ile1025MetfsTer8)). Studies showed innumerably high lymphocyte subsets, elevated double-negative T (DNT) cells (2.7% lymphocytes), but no evidence of lymphoma. As TET2 deficiency causes global DNA hypermethylation, we hypothesized that treatment with a hypomethylating agent would ameliorate her symptoms. Methods After informed consent, the patient was initiated on decitabine, a cytosine analog and DNA methyltransferase inhibitor. For molecular characterization of TET2 deficiency and effects of decitabine, we collected peripheral blood mononuclear cells (PBMC) from the proband pre- and post-decitabine to compare with age-matched controls. Whole-genome sequencing with real-time methylation calling (5-methylcytosine [5mC] and 5-hydroxymethylcytosine [5hmC] is being performed on PromethION (Oxford Nanopore Technologies, ONT). Single-cell RNA sequencing will be performed with the 10X Genomics 3′ Universal Gene Expression kit on a 10X Chromium. Data will be analyzed with ONT workflows. Results The patient was treated with intravenous decitabine 100 mg/m2/month, which temporarily improved serum albumin from 1 g/dL to 2.5 g/dL with reversion between cycles. Despite transient lab changes, the patient was weaned off respiratory support with improved lymphadenopathy, ascites, and edema. For more consistent disease control, we attempted weekly infusions of 25 mg/m2, causing serum albumin to normalize (3 g/dL), without exogenous albumin, and improved proteinuria (∼100,000 to 1,100 mg protein/g creatinine). Lymphocyte subsets largely normalized, DNT cells improved to 2.2%, and CD27+ memory B cells increased (5.7% to 12.8%). The patient was discharged at 9 months old. Conclusions This is the first report of a patient with TET2 deficiency being treated safely and efficaciously with a hypomethylating agent. Ongoing studies will provide the first characterization of whole-genome DNA methylation and concomitant perturbations in RNA expression in TET2 deficiency and demonstrate how these are altered by decitabine. Figure 1. Serum albumin in a patient with germline TET2 deficiency pre- and post-decitabine.