UNC13D c.2588G>A 核苷酸变异损害成人起病 EBV 相关噬血细胞性淋巴组织细胞增生症中的 NK 细胞细胞毒性：一项家系研究

UNC13D , 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 UNC13D , 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 UNC13D 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 UNC13D 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 UNC13D c. 2588G>A variant could partially impair NK cell cytotoxicity, in contrast to the completely recessive inheritance observed with UNC13D c. 1978_1979insATTACCG and other familial HLH-related variants.

In addition, to explore the implication of UNC13D 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 UNC13D 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 UNC13D c. 2588G>A variant and expands our understanding of the genetic basis of adult-onset HLH.