title: De novomutation and somatic mosaicism of gene mutation in type 2A, 2B and 2M VWD.
abstract: BACKGROUND
  Von Willebrand disease (VWD) is not uncommon in Taiwan. In type 2 or type 3 VWD hemorrhagic symptoms are severer and laboratory data relatively more distinctive.De novomutation and somatic mosaicism of type 2 VWD gene were rarely reported. Therefore clinical, laboratory and genetic studies of only type 2A, 2B and 2M VWD will be presented and issues ofde novomutation and somatic mosaicism will be explored.
  
  
  METHODS
  Fifty-four patients belonging to 23 unrelated families from all around the country in whom type 2 VWD exclusive of type 2N has been diagnosed not only by clinical and routine laboratory studies but also by genetic confirmation during 1990-2015 were investigated. A novel technique named amplification refractory mutation system-quantitative polymerase chain reaction (ARMS-qPCR) was used to confirm the presence of somatic mosaicism. Informed consent was obtained for study.
  
  
  RESULTS
  De novomutation was identified in 4 families among 15 families (26.7 %) in whom family members including parents were available for examination. All their parents were free from bleeding symptoms and had no similar mutation as their respective affected daughter. An interesting example of somatic mosaicism of VWF gene mutation was found in a large family with type 2A VWD. The father carrying a mutated VWF gene, p.Arg1597Trp, transmitted this mutation to his 3 daughters, 1 son, 3 granddaughters and 2 grandsons. However, the father had normal laboratory findings and experienced no abnormal bleeding, while his offspring who inherited the mutation showed abnormal laboratory findings compatible with type 2A VWD and had history of abnormal bleedings. ARMS-qPCR revealed that the father had only 25.5 % mutant in his blood cells and 31.1 % mutant in his oral mucosal cells, while all his offspring had about 49 % mutant in their blood cells.
  
  
  CONCLUSIONS
  De novomutation of type 2 VWD gene was identified in 4 out of 15 families (26.7 %) examined. Since only one child was affected in each family, germline mosaicism was not likely. A somatic mosaicism of type 2A VWD gene was documented in a big family by a newly in-house developed technique ARMS-qPCR.
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100 Taiwan.|Department of Internal Medicine, Changhua Christian Hospital, Changhua, 500 Taiwan.
authors.forename: Ming-Ching
authors.initials: MC
authors.lastname: Shen
authors.affiliation: Department of Genomic Medicine, Changhua Christian Hospital, Changhua, 500 Taiwan.|Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, 100 Taiwan.|Department of Medical Genetics, National Taiwan University Hospital, Taipei, 100 Taiwan.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Genomic Medicine, Changhua Christian Hospital, Changhua, 500 Taiwan.
authors.forename: Gwo-Chin
authors.initials: GC
authors.lastname: Ma
authors.affiliation: Department of Genomic Medicine, Changhua Christian Hospital, Changhua, 500 Taiwan.
authors.forename: Shun-Ping
authors.initials: SP
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, Changhua Christian Hospital, Changhua, 500 Taiwan.
authors.forename: Ching-Yeh
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, Changhua Christian Hospital, Changhua, 500 Taiwan.
authors.forename: Bo-Do
authors.initials: BD
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, Changhua Christian Hospital, Changhua, 500 Taiwan.
authors.forename: Han-Ni
authors.initials: HN
authors.lastname: Hsieh
keywords: De novo mutation; Novel mutation; Somatic mosaicism; Type 2A VWD