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 have also been 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 FY2017, we reported two new immunodeficiency diseases. First, in an international collaboration, we identified a new disease of EBV susceptibility and lymphoma due to loss-of-function mutations in CD70, a costimulatory molecule important for EBV-specific T cell responses. Second, we identified a new disease of innate immunity caused by genetic defects in a sensor of viral double-stranded RNA called MDA5, which is encoded by the IFIH1 gene and which leads to rhinovirus susceptibility. We also contributed to a report of a new disease of protein-losing enteropathy due to loss-of-function mutations in CD55 that is involved in complement regulation (CHAPLE syndrome, CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy). Finally, we contributed to reports of new mutations associated with PASLI disease, as well as association of an IFITM3 variant with severe influenza virus infections. We completed enrollment in a collaborative study with the NIH Clinical Center and NHGRI that is aimed not only at identifying underlying monogenetic causes of novel immune disorders, but also is aimed at integrating into clinical practice incidental genetic findings found on whole exome sequencing. Finally, other ongoing collaborative studies involve investigating the natural history and optimal treatment for PASLI, CHAI, STAT3 gain-of-function, BENTA, and XMEN diseases.
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