DOCK11 was first reported in relation to X-linked early-onset autoimmune disorder due to DOCK11 partial deficiency in 2023 (Boussard C, et al., PMID: 36952639). This is a heterogeneous disorder characterized by early-onset autoinflammation and autoimmunity, including Evans syndrome, juvenile rheumatoid arthritis, systemic lupus erythematosus, gastrointestinal disease, skin inflammation, and autoantibody production.
Twelve variants (missense, nonsense, and splice variants) that have been reported in 12 probands in 3 publications (PMIDs: 36952639, 37342957, 40274249) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by animal models, expression studies, and in vitro functional assays in cell lines and patient cells (PMIDs: 36952639, 37342957, 40274249). DOCK11 has been demonstrated to have a role in T-cell filopodia formation and migration (PMID: 37342957). Patient T cells carrying DOCK11 variants demonstrate decreased DOCK11 expression and defects in T-cell proliferation, migration, and cytokine production (PMID: 36952639, 37342957, 40274249). In addition, a DOCK11-knockout mouse model and DOCK11-knockdown Zebrafish model both recapitulated aspects of human disease (PMID: 37342957).
In summary, there is strong evidence to support the relationship between DOCK11 and X-linked early-onset autoimmune disorder due to DOCK11 partial deficiency. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted.
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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