| Domain | Summary | Evidence type | Key citations |
|---|---|---|---|
| Evidence base | Ultra-rare monogenic inborn error of immunity described in a foundational 2019 report of 3 affected individuals from 2 unrelated families; later literature is mainly review/contextual, with no large dedicated cohort or trial identified. | Direct human cohort + later expert review | (pqac-00000008, pqac-00000027, pqac-00000029) |
| Inheritance / variants | Autosomal recessive pattern supported by biallelic homozygous DEF6 missense variants in consanguineous families: family A c.991G>A p.Glu331Lys (2 siblings), family B c.628T>G p.Tyr210Asp (1 patient). Both were reported as damaging and absent in homozygous state in ExAC/gnomAD/TOPMed in the source paper. | Direct human genetic evidence | (pqac-00000009, pqac-00000028) |
| Core phenotype | Early-onset systemic autoimmunity with immunodeficiency: severe enteropathy/diarrhea, bowel inflammation, hepatosplenomegaly or hepatomegaly/cholestasis, cardiomyopathy/cardiac malformations, recurrent infections, and autoimmune hematologic disease in one patient. One sibling died in infancy from cardiomyopathy-related multiorgan failure. | Direct human clinical evidence | (pqac-00000008, pqac-00000010, pqac-00000012) |
| Laboratory phenotype | Reported abnormalities included reduced CD8+ T cells, reduced Tregs, few class-switched B cells, decreased mature NK cells, hypogammaglobulinemia with poor vaccine responses, positive autoantibodies/autoimmune markers (ANCA, cardiolipin, beta2-glycoprotein, positive direct Coombs), while neutrophil phagocytosis and oxidative burst were normal. | Direct human immunology/lab evidence | (pqac-00000008, pqac-00000009, pqac-00000028) |
| Mechanism | DEF6 deficiency impairs CTLA-4 homeostasis in T cells by disrupting DEF6-RAB11 interaction, reducing RAB11+CTLA-4 recycling vesicles, CTLA-4 cycling, ligand uptake/transendocytosis, and functional surface CTLA-4 availability. Variants also reduce DEF6 protein abundance/stability, especially p.Tyr210Asp. | Direct human cellular evidence + engineered cell validation | (pqac-00000013, pqac-00000014, pqac-00000016, pqac-00000017, pqac-00000018) |
| Diagnosis | Supported approach from available evidence: molecular sequencing confirming biallelic DEF6 variants in patients with early immune dysregulation plus functional corroboration using CTLA-4 trafficking/cycling or ligand-uptake assays in T cells when available. No disease-specific formal diagnostic criteria, screening program, or validated biomarker panel was identified. | Direct human evidence + expert extrapolation | (pqac-00000022, pqac-00000023, pqac-00000026) |
| Treatment | Directly reported care included immunoglobulin replacement, antibiotics/anti-infectives, conventional immunosuppression for autoimmune complications, and targeted CTLA-4-Ig (abatacept). One patient treated from 15 months had marked improvement and sustained remission over ~4 years. No DEF6-specific HSCT, gene therapy, RNA therapy, or trial evidence was identified. | Direct human treatment evidence | (pqac-00000021, pqac-00000022, pqac-00000023) |
| Prognosis | Clinical course appears severe and variable: 1 of 3 known patients died in infancy; another had sustained remission of autoimmunity and stable cardiorespiratory status on abatacept; persistent infection susceptibility remained a concern despite supportive therapy. Long-term survival, penetrance, and natural-history estimates are unknown. | Direct human follow-up evidence | (pqac-00000008, pqac-00000010, pqac-00000021) |
| Major knowledge gaps | No verified disease-specific population prevalence/incidence, no large natural-history study, no robust genotype-phenotype map, no established penetrance estimate, no DEF6-specific interventional trial, no validated prevention strategy, and no standardized diagnostic or management guideline. Mouse/model work suggests broader roles in T-cell signaling, TFH/TH17 biology, lupus-like disease, arthritis, and osteoclastogenesis, but these are not yet equivalent to proven human disease features. | Explicit gap statement with model/extrapolation boundary | (pqac-00000025, pqac-00000034, pqac-00000037, pqac-00000038) |


*Table: This table provides a compact disease knowledge-base summary for DEF6 deficiency, separating direct human evidence from model-based extrapolation. It is useful for quickly identifying what is established, what is clinically actionable, and where major evidence gaps remain.*