Identification of Causative Genes and Mutations in Korean Familial Hemophagocytic Lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and genetically heterogeneous disorder characterized by immune dysregulation with a defect in apoptosis triggering and in natural killer and cytotoxic T lymphocyte cellular cytotoxicity. It occurs mostly in infancy and early childhood, and without treatment, is invariably fatal with a median survival of less than 2 months after diagnosis. Only early hematopoietic stem cell transplantation (HSCT) has been shown to cure the disease. The molecular genetic defect causing FHL has been intensively investigated for recent years and classification of FHL according to the genetic abnormality has been tried. It has been noted that some mutations appear to be more frequent in patients from a certain geographical region, but there is no data available for the genetic background of Korean FHL patients. The aim of this study was to identify causative gene(s) and mutation(s) by mutation analyses of three known HLH causative genes, namely PRF1, UNC13D, and STX11 in Korean FHL patients. We also analyzed whether there were genotype-phenotype correlations among these genetic subtypes, and intended to provide critical information for the decision making for timely and most appropriate treatment of FHL patients. Fifteen patients with suspected FHL were recruited from the Korean National Registry of HLH between January 2007 and March 2008. By using genomic DNA samples extracted from peripheral blood leukocytes, direct sequencing was performed in all the exons and their flanking intronic sequences of the PRF1 gene, UNC13D gene, and STX11 gene by genetic analyzer. The correlation between clinical features and genetic subtypes was investigated. Of the 15 HLH patients, 8 mutations of UNC13D gene were found in 5 patients, and 5 of the 8 mutations were novel (Q98X, IVS24+1G>A, IVS21-2A>G, IVS30+5G>A, c.1693delG). Neither PRF1 nor STX11 mutation was identified. IVS9-1G>C, one of the previously reported UNC13D mutations, was found in 3 patients. The clinical features of the patients with UNC13D mutation were associated with earlier age of disease onset (median: 2 months, versus 21 months), more frequent involvement of central nervous system (60% versus 20%), and poorer treatment response (complete response rate 20% versus 70%) than those of FHL patients without UNC13D mutation. This study is the first report to indicate UNC13D mutations as a molecular genetic cause in Korean patients with FHL by direct gene sequencing. The novel UNC13D mutations found in Korean FHL patients implicate the possible presence of an ethnical difference in the genetic background of FHL development. Further study with a larger number of FHL patients would be needed to identify other potential causative genes and mutations and to clarify the genotype-phenotype correlation for each mutation. Moreover, earlier detection of UNC13D mutation on the basis of this study in a suspected FHL patient would provide important information for the decision making for timely HSCT.