DOCK8 was first reported in relation to autosomal recessive hyper IgE syndrome by two groups in 2009 (PMIDs:19776401, 20004785). DOCK8 deficiency is associated with a combined immunodeficiency (CID) phenotype characterized by recurrent cutaneous infections, increased serum IgE levels, and severe atopic disease. Deficiency of DOCK8 is associated with defects in immune cell differentiation, migration, survival and activation. Heterogeneity of disease phenotype severity has been reported and is most likely due to germline variant reversion due to somatic repair (PMIDs:24797421, 33290277). These germline reversions of DOCK8 variants have been shown to reduce eosinophilia and atopy in patients, with rare patients being effectively cured of disease. However, only hematopoietic stem cell transplant has been shown to be curative in the majority of patients. Over 30 unique DOCK8 variants have been reported and are predominantly composed of frameshift, nonsense, splicing, indel variants along with large deletions. Evidence supporting this gene-disease relationship includes case-level and experimental data. Fifteen unique variants from 14 probands in 4 publications were curated (PMIDs:19776401, 20622910, 20004785, 33290277). More evidence is available in the literature, but the maximum score for genetic evidence has been reached (12 pts). Experimentally, in-vitro studies and animal models deficient for DOCK8 support this gene-disease relationship. DOCK8 null mouse models recapitulate defects of lymphocytes seen in patients (PMIDs:19898472, 22006977, 25422492), with in-vitro studies of patient cells showing abnormalities in DOCK8 protein expression and lymphocyte function, morphology and survival (PMID: 27554822, 25422492, 31021819). Somatic reversion of DOCK8 variants have shown to reduce disease phenotype severity and are correlative with the quantity of lymphocytes containing the reverted allele (PMIDs: 24797421, 33290277). In summary, DOCK8 is definitively associated with autosomal recessive hyper IgE syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID-CID Working Group on DATE (SOP Version 8).
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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