NOVAL COMBINED IMMUNODEFICIENCY, HYPOGAMMAGLOBINEMIA, BONE MARROW FAILURE AND RADIOSENSITIVITY DUE TO PATHOGENIC MUTATION IN MYSM1

Abstract

Introduction Using radio-sensitivity testing plays a critical role in diagnosis and management of primary immunodeficiency. Case Description We describe a clinical presentation of a premature newborn male who was diagnosed with a rare radio-sensitivity disorder after a positive newborn screen for SCID. Pregnancy was complicated by maternal Type I DM and IUGR. Physical examination remarkable for underweight. The immunological workups confirmed the diagnosis of combined immunodeficiency with B cell aplasia, low T cell and normal NK cell and mildly impaired thymic function. T cell proliferation to mitogen was normal. Negative STR for maternal T cell engraftment. IVIG was started for hypogammaglobinemia. SCID gene sequencing panel was negative. Chromosomal microarray analysis showed region of homozygositiy involving the entire chromosome1. Bone marrow biopsy was done for severe anemia and worsening leukopenia that showed a normal immunophenotyping without abnormal blasts. Radio-sensitivity testing on peripheral blood mononuclear cells demonstrated increased cell death compared to controls following irradiation. Additionally, the patient's unirradiated B-cells radio-sensitivity testing showed spontaneous increased DNA damage signaling. WES identified a homozygous splicing variant in MYSM1 due to paternal uniparental disomy of chromosome1. Discussion MYSM1 is intracellulare enzyme that plays a major role on hematopoietic stem cell maintenance and differentiation in lymphoid cells and bone marrow. In the literature, there were 5 cases reported for pathogenic mutations in MYSM1 that were detected in patients with hypogammaglobulinemia, B-cell deficiency and idiopathic bone marrow failure. 2 patients were shown to have increased radio-sensitivity. We report the first patient with a novel MYSM1 variant who presented with abnormal newborn screen.