title: 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.
abstract: Familial hemophagocytic lymphohistiocytosis (familial HLH or FHL) is a potentially fatal autosomal recessive disorder. Our previous study demonstrated that UNC13D mutations (FHL3) account for ~90 % of FHL in Korea with recurrent splicing mutation c.754-1G>C (IVS9-1G>C). Notably, half of the FHL3 patients had a monoallelic mutation of UNC13D. Deep intronic mutations in UNC13D were recently reported in patients of European descent. In this study, we performed targeted mutation analyses for deep intronic mutations and investigated on the founder effect in FHL3 in Korean patients. The study patients were 72 children with HLH including those with FHL3 previously reported to have a monoallelic UNC13D mutation. All patients were recruited from the Korean Registry of Hemophagocytic Lymphohistiocytosis. In addition to conventional sequencing of FHL2-4, targeted tests for c.118-308C>T and large intronic rearrangement mutations of UNC13D were performed. Haplotype analysis was performed for founder effects using polymorphic markers in the FHL3 locus. FHL mutations were detected in 20 patients (28 %). Seventeen patients had UNC13D mutations (FHL3, 85 %) and three had PRF1 mutations (FHL2, 15 %). UNC13D:c.118-308C>T was detected in ten patients, accounting for 38 % of all mutant alleles of UNC13D, followed by c.754-1G>C (26 %). Haplotype analyses revealed significantly shared haplotypes in both c.118-308C>T and c.754-1G>C, indicating the presence of founder effects. The deep intronic mutation UNC13D:c.118-308C>T accounts for the majority of previously missing mutations and is the most frequent mutation in FHL3 in Korea. Founder effects of two recurrent intronic mutations of UNC13D explain the unusual predominance of FHL3 in Korea.
authors.affiliation: Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, South Korea.
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Seo
authors.forename: Joon-Sup
authors.initials: JS
authors.lastname: Song
authors.forename: Ki-O
authors.initials: KO
authors.lastname: Lee
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Won
authors.forename: Jong-Won
authors.initials: JW
authors.lastname: Kim
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Lee
authors.forename: Keon-Hee
authors.initials: KH
authors.lastname: Yoo
authors.forename: Ki-Woong
authors.initials: KW
authors.lastname: Sung
authors.forename: Hong Hoe
authors.initials: HH
authors.lastname: Koo
authors.forename: Hyoung Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: Hee Young
authors.initials: HY
authors.lastname: Shin
authors.forename: Hyo-Seop
authors.initials: HS
authors.lastname: Ahn
authors.forename: Dong Kyun
authors.initials: DK
authors.lastname: Han
authors.forename: Hoon
authors.initials: H
authors.lastname: Kook
authors.forename: Tai Ju
authors.initials: TJ
authors.lastname: Hwang
authors.forename: Chuhl-Joo
authors.initials: CJ
authors.lastname: Lyu
authors.forename: Mi-Jung
authors.initials: MJ
authors.lastname: Lee
authors.forename: Ji-Yoon
authors.initials: JY
authors.lastname: Kim
authors.forename: Sung-Shik
authors.initials: SS
authors.lastname: Park
authors.forename: Young-Tak
authors.initials: YT
authors.lastname: Lim
authors.forename: Bo-Eun
authors.initials: BE
authors.lastname: Kim
authors.forename: Kyung-Nam
authors.initials: KN
authors.lastname: Koh
authors.forename: Ho Joon
authors.initials: HJ
authors.lastname: Im
authors.forename: Jong Jin
authors.initials: JJ
authors.lastname: Seo
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Kim
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D018703:Founder Effect; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D056910:Republic of Korea / Q000453:epidemiology
chemical_list: D008565:Membrane Proteins; C507969:UNC13D protein, human