STXBP2 was first reported in relation to autosomal recessive familial hemophagocytic lymphohistiocytosis 5 (FHL5) in 2009 (zur Stadt U, et al., 2009, PMID: 19804848). FHL is a hyperinflammatory syndrome caused by an uncontrolled and ineffective proliferation and activation of T lymphocytes, natural killer (NK) cells, and macrophages that infiltrate multiple organs, including liver, spleen, lymph nodes, and central nervous system (CNS), and produce massive amounts of cytokines. This overwhelming hyperimmune status results in a clinical picture characterized by persistent fever, hepatosplenomegaly, pancytopenia, hemophagocytosis in various tissues, coagulation abnormalities, and inflammatory CNS disease. Patients with FHL5 have several unique features, including sensorineural hearing deficit, abnormal bleeding, and severe diarrhea. STXBP2 is involved in intracellular vesicle trafficking and vesicle fusion with membranes, it contributes to the granule exocytosis machinery through interaction with soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins that regulate membrane fusion. The role of STXBP2 in the cytotoxic granule pathway, and how variation in the gene results in FHL5 is currently not understood in detail but the mechanism of disease appears to be loss of function. This curation includes eleven variants (including in-frame deletions, missense, splicing, and frameshift) found in ten probands from two publications (PMIDs: 19804848, 22451424). Additional cases are available in the literature however the maximum score for genetic evidence has been reached. A role in disease is supported by increased expression of STXBP2 in NK cells, T cells, monocytes, and other hematopoietic cells (PMID: 19804848), which is altered in patients (PMID: 19884660), resulting in altered cytotoxicity of patient NK cells and cytotoxic T-lymphocytes (PMID: 19804848). Additionally, degranulation defects were rescued in patient cells with wildtype STXBP2 (PMID: 19884660). STXBP2 is also known to interact with STX11, which has a well established relationship with FHL (PMID: 19804848). In summary STXBP2 is definitively associated with autosomal recessive FHL5. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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