UNC13D – Familial Hemophagocytic Lymphohistiocytosis Type 3

UNC13D encodes Munc13-4, a priming factor for cytotoxic granule exocytosis in NK and T cells. Biallelic pathogenic variants in UNC13D cause familial hemophagocytic lymphohistiocytosis type 3 (FHL3), an autosomal recessive hyperinflammatory syndrome characterized by uncontrolled macrophage activation and defective lymphocyte degranulation ([PMID:14622591]). Loss of Munc13-4 disrupts lytic granule priming at the immunological synapse, leading to life-threatening cytokine storm.

Genetic studies have identified UNC13D mutations in dozens of unrelated families worldwide. In a North American cohort of 1,709 suspected HLH patients, a 253-kb inversion and deep intronic variants c.118-308C>T and c.118-307G>A accounted for 31.6% of FHL3 alleles, explaining 25 additional patients ([PMID:24470399]). A Dutch founder variant c.2695C>T (p.Arg899Ter) was detected in three unrelated patients with genealogical linkage ([PMID:21755595]). Compound splice-site mutations c.753+1G>T and c.2448-13G>A were reported in a 17-month-old presenting with EBV-triggered HLH ([PMID:24825797]).

The variant spectrum includes splice-site, deep intronic, missense, nonsense, and structural changes. A recurrent nonsense variant c.551G>A (p.Trp184Ter) illustrates loss-of-function via premature termination ([PMID:24470399]). Segregation analysis across >34 unrelated families confirms autosomal recessive inheritance with at least 25 affected relatives co-segregating biallelic UNC13D variants.

Functional assays uniformly demonstrate severe degranulation defects. NK cell and CD57+ CTL degranulation assays show 100% sensitivity and specificity for FHL3, outperforming standard NK assays ([PMID:27896523]). Munc13-4 expression is consistently reduced in patient platelets and lymphocytes, and mutant constructs fail to rescue degranulation in silenced cell models. Mutagenesis of C2 domains further defines calcium-dependent priming deficits ([PMID:29884704]).

No credible conflicting evidence has been reported. Diagnostic evaluation should integrate comprehensive UNC13D sequencing—including coding and noncoding regions—and functional degranulation testing. Early molecular and functional confirmation enables prompt initiation of HLH-2004 protocol and hematopoietic stem cell transplantation.

Key Take-home: UNC13D variants are definitively associated with FHL3; combined genetic and functional testing is essential for accurate diagnosis and management.

References

• Cell • 2003 • Getting secretory granules ready for prime time PMID:14622591
• 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
• Pediatric blood & cancer • 2012 • A novel Dutch mutation in UNC13D reveals an essential role of the C2B domain in munc13-4 function PMID:21755595
• Journal of clinical immunology • 2017 • A CD57+ CTL Degranulation Assay Effectively Identifies Familial Hemophagocytic Lymphohistiocytosis Type 3 Patients PMID:27896523
• Clinical immunology (Orlando, Fla.) • 2014 • Novel and atypical splicing mutation in a compound heterozygous UNC13D defect presenting in Familial Hemophagocytic Lymphohistiocytosis triggered by EBV infection PMID:24825797

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