UNC13D – Hereditary Hemophagocytic Lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) is an autosomal recessive hyperinflammatory disorder caused by biallelic pathogenic variants in UNC13D, encoding Munc13-4. Patients present in infancy or childhood with fever, splenomegaly, cytopenias, hyperferritinemia, hypofibrinogenemia, and variable central nervous system involvement. Deep intronic and structural variants may underlie otherwise unexplained cases, highlighting the need for comprehensive genetic testing.

1 Clinical Validity

Inheritance mode: Autosomal recessive
UNC13D deficiency has been confirmed in >80 probands from >60 unrelated families worldwide, including homozygous and compound heterozygous LoF variants that segregate with disease in multiple affected sibships (PMID:15466010, PMID:15632205, PMID:17993578). Founder splice-site mutations c.754-1G>C and deep intronic c.118-308C>T account for a large fraction of Korean FHL3 cases (PMID:23180437).

2 Genetic Evidence

Segregation analyses across consanguineous and non-consanguineous families demonstrate co-segregation of UNC13D mutations with disease. A recurrent canonical splice-site variant, c.753+1G>T, abolishes correct mRNA splicing and leads to absent Munc13-4 protein in patient cells (PMID:15466010). The allelic spectrum includes nonsense, frameshift, splice-site, missense, inversion, and deep intronic mutations, cumulatively accounting for ~25% of PRF1/STX11-negative FHL families (PMID:17993578). Recurrent founder alleles support a robust genotype-phenotype correlation.

3 Functional Evidence

Munc13-4 physically interacts with Rab27a to prime secretory granules for Ca²⁺-dependent exocytosis in NK and CD8⁺ T cells. Loss of Munc13-4 impairs CTL and NK cell degranulation, as shown by cytotoxicity assays and β-hexosaminidase release in RBL-2H3 cells (PMID:14622591, PMID:14699162). Deep intronic and inversion mutations abolish lymphocyte-specific UNC13D transcription and Munc13-4 expression, confirming pathogenicity of non-coding variants (PMID:21931115).

4 Clinical Translation & Outcomes

Early molecular diagnosis of UNC13D mutations expedites initiation of HLH-2004–based chemoimmunotherapy and timely allogeneic hematopoietic stem cell transplantation, which dramatically improves survival. UNC13D testing is recommended in patients with atypical CNS presentation mimicking ADEM (PMID:19023578) and in adult-onset HLH cases with hypomorphic mutations (PMID:21881043).

5 Conclusion & Take-Home

The gene–disease association between UNC13D and FHL3 is Definitive based on extensive genetic and functional concordance accumulated over >15 years. Key Take-Home: UNC13D mutation screening should be performed promptly in pediatric and adult patients with suspected HLH to guide curative HSCT.

References

• 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
• Blood • 2005 • Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions PMID:15632205
• Journal of medical genetics • 2008 • Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis PMID:17993578
• Blood • 2011 • Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D PMID:21931115
• Annals of hematology • 2013 • Founder effects in two predominant intronic mutations of UNC13D, c.118-308C>T and c.754-1G>C underlie the unusual predominance of type 3 familial hemophagocytic lymphohistiocytosis (FHL3) in Korea PMID:23180437
• Cell • 2003 • Getting secretory granules ready for prime time PMID:14622591
• The Journal of biological chemistry • 2004 • Munc13-4 is a GTP-Rab27-binding protein regulating dense core granule secretion in platelets PMID:14699162
• Child's nervous system • 2009 • Diagnostic challenges in a child with familial hemophagocytic lymphohistiocytosis type 3 presenting with fulminant neurological disease PMID:19023578
• Blood • 2011 • Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH PMID:21881043

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