title: DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum.
abstract: We detected disease-causing mutations in 585 of 598 individuals (98 %) with typical features of osteogenesis imperfecta (OI). In mild OI, only collagen type I encoding genes were involved. In moderate to severe OI, mutations in 12 different genes were found; 11 % of these patients had mutations in recessive genes.
  
  
  
  OI is usually caused by mutations in COL1A1 or COL1A2, the genes encoding collagen type I alpha chains, but mutations in at least 16 other genes have also been associated with OI. It is presently unknown what proportion of individuals with clinical features of OI has a disease-causing mutation in one of these genes.
  
  
  
  DNA sequence analysis was performed on 598 individuals from 487 families who had a typical OI phenotype. OI type I was diagnosed in 43 % of individuals, and 57 % had moderate to severe OI, defined as OI types other than type I.
  
  
  
  Disease-causing variants were detected in 97 % of individuals with OI type I and in 99 % of patients with moderate to severe OI. All mutations found in OI type I were dominant and exclusively affected COL1A1 or COL1A2. In moderate to severe OI, dominant mutations were found in COL1A1/COL1A2 (77 %), IFITM5 (9 %), and P4HB (0.6 %). Mutations in one of the recessive OI-associated gene were observed in 12 % of individuals with moderate to severe OI. The genes most frequently involved in recessive OI were SERPINF1 (4.0 % of individuals with moderate to severe OI) and CRTAP (2.9 %).
  
  
  
  DNA sequence analysis of currently known OI-associated genes identifies disease-causing variants in almost all individuals with a typical OI phenotype. About 20 % of individuals with moderate to severe OI had mutations in genes other than COL1A1/COL1A2.
authors: Shriners Hospital for Children and McGill University, 1003 Decarie, Montreal, H3G 1A6, Québec, Canada.
authors: G
authors: G
authors: Bardai
authors: Shriners Hospital for Children and McGill University, 1003 Decarie, Montreal, H3G 1A6, Québec, Canada.
authors: P
authors: P
authors: Moffatt
authors: Shriners Hospital for Children and McGill University, 1003 Decarie, Montreal, H3G 1A6, Québec, Canada.
authors: F H
authors: FH
authors: Glorieux
authors: Shriners Hospital for Children and McGill University, 1003 Decarie, Montreal, H3G 1A6, Québec, Canada. frauch@shriners.mcgill.ca.
authors: F
authors: F
authors: Rauch
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D004252:DNA Mutational Analysis; D006801:Humans; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D055815:Young Adult
chemical_list: C000601279:COL1A2 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain
keywords: Children; Fractures; Mutations; Next-generation sequencing; Osteogenesis imperfecta