Defining New Human Immunodeficiency and Immunodysregulation Disorders

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Besides unique patients with immunodeficiency and immunodysregulation disorders lacking known diagnoses, our intake includes patients with combined immunodeficiency, variants of hyper-IgE syndrome, variants of autoimmune lymphoproliferative syndrome (ALPS) or caspase-8-deficiency state (CEDS), common variable immunodeficiency (CVID), X-linked Magnesium defect with EBV infection and Neoplasia (XMEN), variants of PASLI (p110 delta activation mutation causing senescent T cells, lymphadenopathy, and immunodeficiency) disease, and Evans syndrome. Our evaluation includes functional screening and gene sequencing, and a subset of patients is also being intensively studied using biochemical analyses, gene expression microarrays, flow cytometric analyses, in vitro functional tests, and other technologies. These experiments have provided leads for sequencing of new candidate genes not previously associated with disease. Additionally, we are using comparative genomic hybridization (CGH) arrays, whole exome sequencing, and other technologies to determine genetic causes of new immunological diseases in an unbiased manner. In FY2014, using these approaches, we identified from our hyperimmunoglobulinemia E cohort a new disease. This disease is characterized by immune deficiency with recurrent pulmonary and other infections, severe atopic dermatitis and cutaneous vasculitis, autoimmunity including glomerulonephritis and cytopenias, motor and neurocognitive impairment, and lymphoma. We found that this disease is caused by autosomal recessive hypomorphic mutations in the phosphoglucomutase 3 (PGM3) gene, making this a new congenital disorder of glycosylation. The defect in glycolylation affects various immune functions, including the expression of CTLA4, a regulator that normally dampens adaptive immune responses to prevent autoimmunity. Our findings will improve diagnosis, provide new insight into how glycosylation regulates the immune system works to prevent allergy and infection, and also suggest potential therapeutic approaches.