Founder Effects of a Recurrent Splicing Mutation IVS9-1G>C of the UNC13D Gene in Korean Patients with Familial Hemophagocytic Lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL) is a potentially fatal disease with an autosomal recessive inheritance. Mutations in the UNF13D gene (FHL3) are the major genetic background of Korean patients with FHL (∼90). In particular, a single splicing mutation, IVS9-1G>C, is recurrent and accounts for the majority of mutant alleles (>50%), suggesting a founder effect. In this regard, the authors investigated the signature of founder effect in Korean patients with FHL3.

The study patients were 17 pediatric patients with FHL3 recruited from the Korean Registry of HLH between January 2007 and June 2010. Nine patients had 1 (n=8) or 2 (n=1) mutant alleles of IVS9-1G>C. Haplotypes of the genomic region of UNC13D were reconstructed using the genotype information of short tandem repeat (STR) and single nucleotide polymorphism (SNP) markers in a set of 192 control chromosomes of Korean descent. The haplotypes of the 17 patients were assigned and analyzed with respect to the mutation status.

Fifteen haplotypes (Ht1-Ht15) were reconstructed based on the genotype data from 5 common SNPs of UNC13D (rs7210574, rs2290770, rs7223416, rs3744007, and rs3744010) in the control group. Haplotype analyses in the control group demonstrated that Ht3 was remarkably more prevalent in the patient group than in the control group (55.0% vs. 31.3%), and all 9 patients with IVS9-1G>C had Ht3. In addition, all patients with IVS9-1G>C except one had the 258 allele of a polymorphic STR marker near UNC13D (DS19S1839).

The results suggested a founder effect in the recurring mutation IVS9-1G>C of UNC13D in Korean patients. This observation may explain the unusually high proportion of FHL3 in Korea.

No relevant conflicts of interest to declare.