title: A pericentric inversion of chromosome X disruptingF8and resulting in haemophilia A.
abstract: OBJECTIVE
  The frequency of X chromosome pericentric inversion is much less than that of autosome chromosome. We hereby characterise a pericentric inversion of X chromosome associated with severe factor VIII (FVIII) deficiency in a sporadic haemophilia A (HA) pedigree.
  
  
  METHODS
  PCR primer walking and genome walking strategies were adopted to identify the exact breakpoints of the inversion. Copy number variations (CNVs) of theF8and the whole chromosomes were detected by AccuCopy and Affymetrix CytoScan High Definition (HD) assays, respectively. A karyotype analysis was performed by cytogenetic G banding technique.
  
  
  RESULTS
  We identified a previously undescribed type of pericentric inversion of the X chromosome [inv(X)(p11.21q28)] in the proband with FVIII:C <1%. One breakpoint was located in the intron 7 of theF8, which disrupted the transcription of theF8,and the other located in the upstream of thePFKFB1of the X chromosome. The inversion segment was approximately 64.4% of the total chromosomal length. The karyotype analysis of the X chromosome confirmed the pericentric inversion of the X chromosome in the proband and his mother. A haplotype analysis traced the inversion to his maternal grandfather, who was not a somatic mosaic of the inversion. This finding indicated that the causative mutation may originate from his germ cells or a rare possibility of germ-cell mosaicism.
  
  
  CONCLUSIONS
  The characterisation of pericentric inversion involvingF8extended the molecular mechanisms causing HA. The pericentric inversion rearrangement involvesF8by non-homologous end joining is responsible for pathogensis of severe HA.
authors.affiliation: Department of Laboratory Medicine, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China.|State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xin
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Department of Laboratory Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Qiulan
authors.initials: Q
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Changming
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Jiang
mesh_terms: D002675:Child, Preschool; D056905:Chromosome Breakpoints; D007446:Chromosome Inversion / Q000235:genetics*; D041321:Chromosomes, Human, X; D005091:Exons / Q000235:genetics; D005169:Factor VIII / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D059785:Karyotype; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010732:Phosphofructokinase-1 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D012333:RNA, Messenger; C078147:F8 protein, human; D005169:Factor VIII; D010732:Phosphofructokinase-1
keywords: BLEEDING DISORDERS; GENETICS; HAEMOPHILIA; THROMBOPHILIA