DOCK11 – Autoinflammatory disease, multisystem, with immune dysregulation, X-linked

DOCK11 deficiency is an X-linked recessive multisystem autoinflammatory disorder characterized by immune dysregulation, early-onset autoimmunity, cytopenias, systemic inflammation and acute liver failure. Fourteen male probands from 13 unrelated families harbor hemizygous loss-of-function or missense DOCK11 variants ([PMID:37342957]; [PMID:36952639]; [PMID:40274249]; [PMID:40107756]). This association meets a Strong ClinGen gene–disease validity based on multiple unrelated families, consistent variant segregation, and concordant functional data.

Genetically, DOCK11 deficiency follows X-linked recessive inheritance. Reported variants include two truncating alleles (c.75dup (p.Glu26Ter), c.3754C>T (p.Gln1252Ter)) and six missense changes (including c.5120G>C (p.Trp1707Ser)) affecting evolutionarily conserved residues. No recurrent or founder variants have been described and no obligate carrier segregation beyond the probands has been reported.

Functional assays define a loss-of-function mechanism. Patient-derived T cells exhibit impaired CDC42 activation, defective filopodia formation, abnormal migration and heightened NFATc1 nuclear translocation. Dock11-knockout mice and zebrafish recapitulate immune hyperactivation, proinflammatory cytokine release, and anisopoikilocytosis, with anemia phenotypes rescued by constitutively active CDC42 ([PMID:37342957]; [PMID:36952639]).

No published evidence disputes this gene–disease relationship. Expression studies of DOCK11 isoforms across human tissues further support its key role in hematopoietic and immune cells.

In summary, hemizygous DOCK11 variants cause a clinically recognizable X-linked autoinflammatory syndrome with immune dysregulation, validated by robust genetic and experimental data. This knowledge enables targeted genetic testing, informs management of immune and hepatic manifestations, and guides future therapeutic development.

References

• BMJ case reports • 2025 • DOCK11 deficiency-related immune dysregulation leading to paediatric acute liver failure. PMID:40107756
• The New England journal of medicine • 2023 • Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency. PMID:37342957
• Blood • 2023 • DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity. PMID:36952639
• Clinical immunology (Orlando, Fla.) • 2025 • A novel hemizygous nonsense variant in DOCK11 causes systemic inflammation and immunodeficiency. PMID:40274249

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