title: UNC13D is the predominant causative gene with recurrent splicing mutations in Korean patients with familial hemophagocytic lymphohistiocytosis.
abstract: BACKGROUND
  Familial hemophagocytic lymphohistiocytosis is a fatal disease characterized by immune dysregulation from defective function of cytotoxic lymphocytes. Three causative genes have been identified for this autosomal recessive disorder (PRF1, UNC13D, and STX11). We investigated the molecular genetics of familial hemophagocytic lymphohistiocytosis in Korea.
  
  
  METHODS
  Pediatric patients who fulfilled the HLH-2004 criteria were recruited from the Korean Registry for Histiocytosis. Molecular genetic studies were performed on the patients' DNA samples by direct sequencing of all coding exons and flanking sequences of PRF1, UNC13D, and STX11.
  
  
  RESULTS
  Forty patients were studied and familial hemophagocytic lymphohistiocytosis mutations were identified in nine; eight patients had UNC13D mutations (89%) and one had a mutation in PRF1. No patient had a STX11 mutation. Notably, four patients had only one UNC13D mutant allele, suggesting that the other mutation was missed by conventional direct sequencing. All UNC13D mutations were deleterious in nature. One known splicing mutation, c.754-1G>C, was recurrent, accounting for 58% of all the mutant alleles (7/12). Five UNC13D mutations were novel (p.Gln98X, p.Glu565SerfsX7, c.1993-2A>G, c.2367+1G>A, and c.2954+5G>A). The one patient with PRF1 mutation was homozygous for a frameshift mutation (p.Leu364GlufsX93), which was previously reported to be the most frequent PRF1 mutation in Japan.
  
  
  CONCLUSIONS
  This is the first investigation on the molecular genetics of familial hemophagocytic lymphohistiocytosis in Korea. The data showed that UNC13D is the predominant causative gene in the Korean population. The identification of mutations missed by conventional sequencing would better delineate the mutation spectrum and help to establish the optimal molecular diagnostic strategy for familial hemophagocytic lymphohistiocytosis in Korea, which might need an RNA-based screening strategy.
authors.affiliation: Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul, Korea.
authors.forename: Hoi Soo
authors.initials: HS
authors.lastname: Yoon
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Kim
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: Ji-Yoon
authors.initials: JY
authors.lastname: Kim
authors.forename: Young-Tak
authors.initials: YT
authors.lastname: Lim
authors.forename: Keun-Wook
authors.initials: KW
authors.lastname: Bae
authors.forename: Ki-O
authors.initials: KO
authors.lastname: Lee
authors.forename: Ji-Sook
authors.initials: JS
authors.lastname: Shin
authors.forename: Seung-Tae
authors.initials: ST
authors.lastname: Lee
authors.forename: Hae-Sun
authors.initials: HS
authors.lastname: Chung
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Chan-Jeoung
authors.initials: CJ
authors.lastname: Park
authors.forename: Hyun-Sook
authors.initials: HS
authors.lastname: Chi
authors.forename: Ho-Joon
authors.initials: HJ
authors.lastname: Im
authors.forename: Jong Jin
authors.initials: JJ
authors.lastname: Seo
mesh_terms: D000293:Adolescent; D017398:Alternative Splicing / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000032:analysis / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007723:Korea; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics; D011379:Prognosis; D050765:Qa-SNARE Proteins / Q000235:genetics; D012008:Recurrence
chemical_list: D008565:Membrane Proteins; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D050765:Qa-SNARE Proteins; C541732:STX11 protein, human; C507969:UNC13D protein, human; D054353:Perforin; D004247:DNA