title: Nonsynonymous mutations in three anticoagulant genes in Japanese patients with adverse pregnancy outcomes.
abstract: BACKGROUND
  Hereditary thrombophilias may associate with uteroplacental thrombosis leading to adverse pregnancy outcomes. The present study was conducted to reveal the frequency of the low-frequency thrombophilic protein S K196E mutation, as well as the frequency of very rare nonsynonymous mutations in protein S, protein C, and antithrombin genes, in patients with adverse pregnancy outcomes.
  
  
  METHODS
  We enrolled 330 Japanese patients with adverse pregnancy outcomes and divided them into 233 patients with two or more miscarriages and 114 patients with fetal growth restriction (FGR) and/or intrauterine fetal death (IUFD); 17 patients belonged to both groups. We sequenced the entire coding regions of three anticoagulant genes in all 330 patients.
  
  
  RESULTS
  We found that protein S K196E mutation was identified in 4 out of 233 patients with recurrent miscarriage and in 2 out of 114 patients with FGR and/or IUFD. The frequencies of this mutation in these patient groups were not different from that in a Japanese general population. Very rare nonsynonymous mutations were identified in 3.3% (11 out of 330) of patients with adverse pregnancy outcomes.
  
  
  CONCLUSIONS
  Although the low-frequency protein S K196E mutation can increase the risk for venous thromboembolism, it did not increase the risk for adverse pregnancy outcomes even in Japanese.
authors.affiliation: Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan. Electronic address: rneki@ncvc.go.jp.
authors.forename: Reiko
authors.initials: R
authors.lastname: Neki
authors.affiliation: Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan. Electronic address: miyata@ncvc.go.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
authors.affiliation: Department of Maternal Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan.
authors.forename: Tomio
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kokame
authors.affiliation: Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fujita
authors.affiliation: Department of Obstetrics and Gynecology, Kaizuka City Hospital, Kaizuka, Osaka, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Isaka
authors.affiliation: Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshimatsu
mesh_terms: D000026:Abortion, Habitual / Q000235:genetics; D000328:Adult; D005260:Female; D005313:Fetal Death / Q000209:etiology; D005317:Fetal Growth Retardation / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic / Q000235:genetics*; D011256:Pregnancy Outcome / Q000235:genetics*; D011446:Prospective Studies; D017293:Protein S / Q000235:genetics; D050497:Stillbirth / Q000235:genetics; D019851:Thrombophilia / Q000235:genetics
chemical_list: D017293:Protein S
keywords: Fetal death; Fetal growth restriction; Miscarriage; Protein S; Thrombophilia