title: Genotype-phenotype analysis of a rare type of osteogenesis imperfecta in four Chinese families with WNT1 mutations.
abstract: BACKGROUND
  Osteogenesis imperfecta (OI) is a rare inherited disease characterized by increased bone fragility and vulnerability to fractures. Recently, WNT1 is identified as a new candidate gene for OI, here we detect pathogenic mutations in WNT1 and analyze the genotype-phenotype association in four Chinese families with OI.
  
  
  METHODS
  We designed a targeted next generation sequencing panel with known fourteen OI-related genes. We applied the approach to detect pathogenic mutations in OI patients and confirmed the mutations with Sanger sequencing and cosegregation analysis. Clinical fractures, bone mineral density (BMD) and the other clinical manifestations were evaluated. We also observed the effects of bisphosphonates in OI patients with WNT1 mutations.
  
  
  RESULTS
  Four compound heterozygous mutations (c.110T>C; c.505 G>T; c. 385G>A; c.506 G>A) in WNT1 were detected in three unrelated families. These four mutations had not been reported yet. A recurrent homozygous mutation (c.506dupG) was identified in the other two families. These patients had moderate to severe OI, white to blue sclera, absence of dentinogenesis imperfecta and no brain malformation. We did not observe clear genotype-phenotype correlation in WNT1 mutated OI patients. Though bisphosphonates increased BMD in WNT1 related OI patients, height did not increase and fracture continued.
  
  
  CONCLUSIONS
  We reported four novel heterozygous variants and confirmed a previous reported WNT1 mutation in four Chinese families with a clinical diagnosis of OI. Our study expanded OI spectrum and confirmed moderate to severe bone fragility induced by WNT1 defects.
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: BGI Shenzhen: Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin 300308, China; Tianjin Translational Genomics Center, BGI-Tianjin, Tianjin 300308, China.
authors.forename: Lijie
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China.
authors.forename: Doudou
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Lv
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China.
authors.forename: Jianyi
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China.
authors.forename: Weibo
authors.initials: W
authors.lastname: Xia
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China.
authors.forename: Ou
authors.initials: O
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Xing
authors.affiliation: BGI Shenzhen: Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin 300308, China; Tianjin Translational Genomics Center, BGI-Tianjin, Tianjin 300308, China.
authors.lastname: Asan
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China. Electronic address: limeilzh@sina.com.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
mesh_terms: D000293:Adolescent; D002648:Child; D002681:China; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D051155:Wnt1 Protein / Q000235:genetics*
chemical_list: C495247:WNT1 protein, human; D051155:Wnt1 Protein
keywords: Next generation sequencing; Osteogenesis imperfecta; WNT1