UNC13D c.2588G>A Nucleotide Variant Impairs NK-Cell Cytotoxicity in Adult-Onset EBV-Associated Hemophagocytic Lymphohistiocytosis: A Pedigree Study

<i>UNC13D</i>, which encodes the Munc13-4 protein, is a critical gene implicated in type 3 familial hemophagocytic lymphohistiocytosis (HLH). While biallelic nucleotide variants in HLH-related genes, including <i>UNC13D</i>, are traditionally linked to recessive inheritance patterns in HLH, emerging evidence suggests that heterozygous variants may also contribute to the onset of adult-onset HLH. However, the pathogenicity of heterozygous <i>UNC13D</i> variants is still not fully understood. Here, we present a 29-year-old male patient with Epstein-Barr virus (EBV)-triggered adult-onset HLH, who was found to carry compound heterozygous variants in the <i>UNC13D</i> gene (c.2588G>A and c.1978_1979insATTACCG) with complete T/NK cytotoxicity dysfunction. We conducted NK-cell function assay in this pedigree to link the genotype to phenotype and demonstrated that the monoallelic <i>UNC13D</i> c.2588G>A variant could partially impair NK cell cytotoxicity, in contrast to the completely recessive inheritance observed with <i>UNC13D</i> c.1978_1979insATTACCG and other familial HLH-related variants. In addition, to explore the implication of <i>UNC13D</i> c.2588G>A variant in various diseases, we reviewed 16 published studies, including data on 35 patients carrying this variant. Data showed the heterozygous variant of <i>UNC13D</i> c.2588G>A might act as a genetic risk factor predisposing carriers to conditions like HLH, lymphoma, etc. This study underscores the pathogenic role of the <i>UNC13D</i> c.2588G>A variant and expands our understanding of the genetic basis of adult-onset HLH.