title: Exome capture sequencing identifies a novel CCM1 mutation in a Chinese family with multiple cerebral cavernous malformations.
abstract: OBJECTIVE
  Cerebral cavernous malformations (CCMs) are vascular anomalies predominantly in the central nervous system but may include lesions in other tissues, such as the retina, skin and liver. The main clinical manifestations include seizures, hemorrhage, recurrent headaches and focal neurological deficits. Previous studies of familial CCMs (FCCMs) have mainly reported in Hispanic and Caucasian cases. Here, we report on FCCMs in a Chinese family further characterized by a novel CCM1 gene mutation.
  
  
  METHODS
  We investigated clinical and neuroradiological features of a Chinese family of 30 members. Furthermore, we used exome capture sequencing to identify the causing gene. The CCM1 mRNA expression level in three patients of the family and 10 wild-type healthy individuals were detected by real-time quantitative polymerase chain reaction (real-time RT-PCR).
  
  
  RESULTS
  Brain magnetic resonance imaging demonstrated multiple intracranial lesions in seven members. The clinical manifestation of CCM was found in five of these cases, including recurrent headaches, weakness, hemorrhage and seizures. Moreover, we identified a novel nonsense mutation c.1159G>T (p. E387*) in the CCM1 gene in the pedigree. Based on real-time RT-PCR results, we have found that the CCM1 mRNA expression level in three patients was reduced by 35% than that in wild-type healthy individuals.
  
  
  CONCLUSIONS
  Our finding suggests that the novel nonsense mutation c.1159G>T in CCM1 gene is associated with FCCM, and that CCM1 haploinsufficiency may be the underlying mechanism of CCMs. Furthermore, it also demonstrates that exome capture sequencing is an efficient and direct diagnostic tool to identify causes of genetically heterogeneous diseases.
authors.affiliation: a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.|b 2 Institute of Clinical Medicine , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Mao
authors.affiliation: a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.|b 2 Institute of Clinical Medicine , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Zhang
authors.affiliation: a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.|b 2 Institute of Clinical Medicine , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.
authors.forename: Hai-Yang
authors.initials: HY
authors.lastname: Luo
authors.affiliation: a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.
authors.forename: Bo
authors.initials: B
authors.lastname: Song
authors.affiliation: a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.
authors.forename: Yu-Tao
authors.initials: YT
authors.lastname: Liu
authors.affiliation: a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.
authors.forename: Shi-Lei
authors.initials: SL
authors.lastname: Sun
authors.affiliation: a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.|b 2 Institute of Clinical Medicine , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Yang
authors.affiliation: c 3 International Joint Research Laboratory for Cell and Gene Therapy of Henan Province , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.
authors.forename: Pan
authors.initials: P
authors.lastname: Du
authors.affiliation: c 3 International Joint Research Laboratory for Cell and Gene Therapy of Henan Province , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.
authors.forename: Yao-He
authors.initials: YH
authors.lastname: Wang
authors.affiliation: a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.|b 2 Institute of Clinical Medicine , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.
authors.forename: Chang-He
authors.initials: CH
authors.lastname: Shi
authors.affiliation: a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.|b 2 Institute of Clinical Medicine , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Xu
mesh_terms: D000328:Adult; D044466:Asian People; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000000981:diagnostic imaging / Q000235:genetics*; D006801:Humans; D000075927:KRIT1 Protein / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D012333:RNA, Messenger
keywords: CCM1; cerebral cavernous malformations; exome capture sequencing; mRNA decay