UNC13D – Hemophagocytic Syndrome

Hemophagocytic lymphohistiocytosis (HLH; MONDO:0015540) is a life‐threatening hyperinflammatory disorder characterized by fever, cytopenias, splenomegaly, hypercytokinemia, and multiorgan failure. The UNC13D gene (Munc13-4; HGNC:23147) encodes a priming factor essential for lytic granule exocytosis in cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells ([PMID:14622591]). Biallelic UNC13D mutations cause familial HLH type 3 (FHL3) in an autosomal recessive manner, resulting in impaired degranulation and uncontrolled immune activation.

1 Assess Clinical Validity

Overall, the UNC13D–HLH association is classified as Strong. Multiple unrelated probands (>200) across ≥30 families exhibit biallelic UNC13D variants with autosomal recessive inheritance and concordant degranulation defects. Segregation of pathogenic alleles has been demonstrated in at least 6 multiplex families with affected siblings showing HLH phenotypes ([PMID:15466010]). Functional studies in patient CTLs and complemented cell lines confirm loss of Munc13-4 activity.

2 Genetic Evidence

Inheritance mode: Autosomal recessive. Segregation: observed in 6 affected relatives with homozygous or compound heterozygous UNC13D variants. Case series: 36 UNC13D‐variant patients among 265 Chinese HLH cases, including missense, nonsense, splice, and deep intronic changes ([PMID:29665027]). Variant spectrum: >50 distinct alleles reported, comprising nonsense (e.g., p.Trp382Ter), missense, canonical splice (e.g., c.754-1G>C), and deep intronic mutations. A recurrent deep intronic alteration, c.118-307G>A, disrupts a lymphocyte‐specific enhancer in intron 1 and abolishes Munc13-4 expression ([PMID:24470399]).

3 Functional / Experimental Evidence

Munc13-4 is required for priming of cytotoxic granules prior to membrane fusion. CTLs from FHL3 patients exhibit markedly reduced degranulation and CTL/NK cell cytotoxicity, which correlates with absent or truncated Munc13-4 protein ([PMID:15466010]). Complementation of mutant CTLs with wild‐type UNC13D restores degranulation, and mouse models confirm that Munc13-4 deficiency leads to HLH-like pathology. Platelet secretion assays further substantiate a degranulation defect in heterozygous carriers.

4 Conflicting Evidence

No reproducible data dispute the UNC13D–HLH link. Monoallelic variants may present with milder immune dysregulation but do not fulfill HLH diagnostic criteria.

5 Integration & Conclusion

Collectively, genetic and experimental data establish UNC13D as a causative gene in familial HLH type 3. The autosomal recessive inheritance, consistent functional impairment of cytotoxic granule exocytosis, and rescue by complementation underpin a strong gene–disease association. Clinical testing for UNC13D variants, including deep intronic regions, is essential for early diagnosis, genetic counseling, and guiding curative hematopoietic stem cell transplantation.

Key Take-home: UNC13D mutational analysis is a critical diagnostic tool for autosomal recessive HLH, enabling timely intervention to prevent fatal hyperinflammation.

References

• Cell • 2003 • Getting secretory granules ready for prime time. PMID:14622591
• Journal of medical genetics • 2004 • Identification of novel MUNC13-4 mutations in familial haemophagocytic lymphohistiocytosis and functional analysis of MUNC13-4-deficient cytotoxic T lymphocytes. PMID:15466010
• Pediatric blood & cancer • 2014 • The 253-kb inversion and deep intronic mutations in UNC13D are present in North American patients with familial hemophagocytic lymphohistiocytosis 3. PMID:24470399
• Clinical genetics • 2018 • Genetic variant spectrum in 265 Chinese patients with hemophagocytic lymphohistiocytosis: Molecular analyses of PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP. PMID:29665027
• Critical reviews in oncology/hematology • 2005 • Review of hemophagocytic lymphohistiocytosis (HLH) in children with focus on Japanese experiences. PMID:15718147

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