Besides unique patients with immunodeficiency and immunodysregulation disorders lacking known diagnoses, our intake includes patients with combined immunodeficiency, common variable immunodeficiency (CVID), variants of hyper-IgE syndrome or autoimmune lymphoproliferative syndrome (ALPS), Evans syndrome, caspase-8-deficiency state (CEDS), B cell expansion with NF-kB and T cell anergy (BENTA) disease, X-linked Magnesium defect with EBV infection and Neoplasia (XMEN), PASLI (p110 delta activation mutation causing senescent T cells, lymphadenopathy, and immunodeficiency) disease, and CHAI (CTLA4 haploinsufficiency with autoimmune infiltration) disease. Patients with susceptibility to EBV, rhinovirus, influenza virus, respiratory syncytial virus, and other respiratory viruses are also being investigated. 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, whole genome sequencing, and other technologies to determine genetic causes of new immunological diseases in an unbiased manner. In FY2019, we continued our work on investigating the molecular pathogenesis of several as yet undescribed immunodeficiency-immunodysregulation disorders, as well as the natural history and optimal treatment of previously reported rare immunological disorders. We contributed to several studies that were published in FY2019, which are briefly summarized as follows: We contributed to an international multicenter study, which established the utility of Janus-activated kinase (Jak) inhibitors in treating STAT3 or STAT1 gain-of-function immunodysregulation disorders. We contributed to report of a new disease of influenza virus susceptibility due to loss-of-function mutations in IRF9 participating in interferon signaling. We contributed to a report associating MBL mutations with influenza virus disease. We contributed to a report of a new combined immunodeficiency due to loss-of-function mutations in FCHO1. We contributed to two reports extending knowledge about CARD11 gain-of-function mutations causing BENTA disease and EBV manifestations in this disease.
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