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 FY2018, 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 or are in press, which are briefly summarized as follows: We contributed to a report expanding the phenotype associated with RELA haploinsufficiency beyond mucocutaneous ulceration with gastrointestinatl inflammation, to also include lymphoproliferation with autoimmune cytopenias. We contributed to a study investigating the pathogenic mechanism of TRNT1 deficiency, which elucidated how defective tRNA maturation leads to abnormal protein homeostasis and autoinflammation, as well as the utility of TNF antagonists in treating this disorder. 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 the report of a new disease of influenza virus susceptibility due to loss-of-function mutations in a gene participating in interferon signaling. We contributed to a collaborative study with the NIH Clinical Center and NHGRI, which established the feasibility of integrating into clinical practice delivery of incidental genetic findings found on whole exome sequencing performed for other research purposes.
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