STX11 – Familial Hemophagocytic Lymphohistiocytosis Type 4

Syntaxin-11 (STX11) is a t-SNARE protein essential for cytotoxic granule fusion in NK and CD8+ T cells. Biallelic loss-of-function variants in STX11 underlie autosomal recessive familial hemophagocytic lymphohistiocytosis type 4 (FHL4), a hyperinflammatory disorder characterized by fever, splenomegaly, cytopenias, and hemophagocytosis. Genetic and functional studies across diverse populations have established a definitive gene–disease relationship, with consistent concordance between STX11 deficiency and impaired lymphocyte degranulation.

Clinical Validity

STX11–FHL4 meets a Definitive ClinGen classification based on 15 probands identified in independent cohorts (6 probands in 4 families [PMID:16582076], 6 probands across 63 patients [PMID:16278825], 3 probands in North America [PMID:20486178]), segregation of a homozygous nonsense variant in two siblings ([PMID:20486178]), and concordant functional data demonstrating loss of syntaxin-11 expression and NK cell cytotoxicity.

Genetic Evidence

• Inheritance mode: Autosomal recessive.
• Segregation: Two affected siblings homozygous for a truncating variant segregate disease ([PMID:20486178]).
• Case series: 15 unrelated FHL patients harbor biallelic STX11 variants, including nonsense, frameshift, and missense alleles ([PMID:16582076]; [PMID:16278825]; [PMID:20486178]).
• Variant spectrum: Nonsense (e.g., c.73G>T (p.Glu25Ter)), frameshift, splice, and missense (e.g., c.106G>C (p.Glu36Gln)) classes reported.

Functional Evidence

• Mechanism: Loss of STX11 causes defective SNARE-mediated membrane fusion leading to impaired degranulation (haploinsufficiency not implicated).
• In vitro: The p.Glu25Ter variant abolishes syntaxin-11 expression and NK cell degranulation, whereas p.Glu36Gln and p.Glu206Lys preserve expression but variably impact function ([PMID:20486178]).
• Murine model: Stx11−/− mice display profoundly reduced NK and CTL cytotoxicity, develop HLH-like pathology upon LCMV infection, and recapitulate T cell exhaustion seen in human FHL4 ([PMID:23190531]).

Integration & Clinical Utility

The combined genetic and mechanistic evidence definitively supports STX11 testing for AR FHL4. Variants in STX11 should be included in HLH gene panels to enable early diagnosis and guide curative hematopoietic stem cell transplantation.

Key take-home: Autosomal recessive STX11 variants cause FHL4; confirmatory genetic testing with functional assays enables early intervention.

References

• Journal of medical genetics • 2006 • Spectrum and clinical implications of syntaxin 11 gene mutations in familial haemophagocytic lymphohistiocytosis: association with disease-free remissions and haematopoietic malignancies. PMID:16582076
• Human mutation • 2006 • Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. PMID:16278825
• Pediatric blood & cancer • 2010 • STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America. PMID:20486178
• Blood • 2013 • Hemophagocytic lymphohistiocytosis in syntaxin-11-deficient mice: T-cell exhaustion limits fatal disease. PMID:23190531

Evidence Based Scoring (AI generated)