SP110 was first reported in relation to autosomal recessive hepatic veno-occlusive disease-immunodeficiency syndrome (VODI) in 2006 (Rosicioli et al., PMID: 16648851). VODI is characterized by bacterial infections (including Pneumocystis jirovecii, cytomegalovirus, enterovirus, or mucocutaneous candidiasis), hepatomegaly or hepatic failure, liver biopsy results consistent with sinusoidal obstruction syndrome, hypogammaglobulinemia, low intracellular cytokine production, and usually T-cell immunodeficiency with normal circulating T and B cell counts. Some patients displayed a complex neurological phenotype, however the association with SP110 is not fully understood (PMID: 23448538). The mechanism of pathogenicity appears to be homozygous loss of function. The curation of SP110 related to autosomal recessive VODI includes both case-level and experimental evidence. Seven variants (missense, frameshift, and nonsense) reported in seven probands in four publications (PMIDs: 16648851, 22621957, 23448538, 32395362) are included in this curation. The heterozygous parents of probands were all unaffected. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by its enhanced expression in lymphoid tissue (PMID: 16127175), disruption of which is observed by flow cytometry of patient T cell blasts (PMID: 28825155). Additionally, functional alteration is reported in patient cells (PMID: 22621957), such that there is an impairment of B cells to produce IgM, IgG, and IgA. The impaired survival and activation of B cells in vitro most likely explains the hypogammaglobulinemia that is typical of patients with VODI. In summary, there is definitive evidence supporting the relationship between SP110 and autosomal recessive hepatic veno-occlusive disease-immunodeficiency syndrome. 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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