DOCK8 – Combined Immunodeficiency due to DOCK8 Deficiency

Dedicator of cytokinesis 8 (DOCK8) is a guanine nucleotide exchange factor essential for immune cell cytoskeletal dynamics. Biallelic loss-of-function variants in DOCK8 underlie autosomal recessive combined immunodeficiency due to DOCK8 deficiency (MONDO:0009478), characterized by elevated IgE, eosinophilia, eczema, and susceptibility to viral and bacterial infections. The inheritance is autosomal recessive with full penetrance in multiple consanguineous and non-consanguineous families.

Clinical validity is supported by multiple cohort and familial studies. In one large series, 82 patients from 60 families harbored homozygous or compound heterozygous DOCK8 truncating mutations and segregated in an autosomal recessive pattern ([PMID:25724123]). Additional pedigrees include affected sister pairs with large multi-exon deletions detected by MLPA ([PMID:23859592]), confirming segregation of null alleles in trans. These data fulfill ClinGen criteria for a Definitive gene–disease association.

Genetic evidence encompasses over 150 probands with diverse variant classes: frameshifts, nonsense, splice-site, and large deletions. Recurrent alleles such as c.3332delT (p.Phe1113LeufsTer2) have been observed in unrelated families, with complete loss of DOCK8 protein in patient lymphocytes ([PMID:23859592]). Compound heterozygous and homozygous mutations are consistently associated with the phenotype. Variant spectrum reaches the ClinGen genetic cap, warranting a Strong genetic evidence rating.

Functional studies demonstrate that DOCK8 deficiency impairs T-cell expansion, T(H)17 differentiation, and NK cell lytic synapse formation. Patient T cells show a TH2 bias at the expense of TH1/TH17 lineages ([PMID:27554822]), while NK cells fail to accumulate F-actin at immunologic synapses ([PMID:20004785]). Hematopoietic stem cell transplantation reverses immunologic defects and resolves clinical disease, providing rescue evidence in human cells and clinical cure ([PMID:31021819]). These concordant data support a Strong functional evidence rating.

No credible conflicting reports dispute the association. Variable somatic reversion in some patients modulates severity but does not negate causality. Reported atypical presentations underscore the need for molecular confirmation in suspected cases.

Integration of extensive genetic and experimental data establishes a Definitive association between DOCK8 and combined immunodeficiency due to DOCK8 deficiency. Early genetic testing in patients with refractory eczema, sinopulmonary infections, and elevated IgE is critical, as allogeneic hematopoietic stem cell transplantation offers definitive cure.

Key Take-home: Genetic and functional concordance define DOCK8 deficiency as a clinically actionable autosomal recessive immunodeficiency curable by stem cell transplantation.

References

• The Journal of allergy and clinical immunology | 2015 | The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency. PMID:25724123
• The Journal of allergy and clinical immunology | 2017 | Dedicator of cytokinesis 8-deficient CD4+ T cells are biased to a TH2 effector fate at the expense of TH1 and TH17 cells PMID:27554822
• The Journal of allergy and clinical immunology | 2009 | Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. PMID:20004785
• JCI insight | 2019 | Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients. PMID:31021819
• European Journal of haematology | 2013 | Novel dedicator of cytokinesis 8 mutations identified by multiplex ligation-dependent probe amplification. PMID:23859592

Evidence Based Scoring (AI generated)