Genotype-phenotype correlations in nonlethal osteogenesis imperfecta caused by mutations in the helical domain of collagen type I

Osteogenesis imperfecta (OI) is a heritable disorder with bone fragility that is often associated with short stature, tooth abnormalities (dentinogenesis imperfecta), and blue sclera. The most common mutations associated with OI result from the substitution for glycine by another amino acid in the triple helical domain of either the alpha 1 or the alpha 2 chain of collagen type I. In this study, we compared the results of genotype analysis and clinical examination in 161 OI patients (median age: 13 years) who had glycine mutations in the triple helical domain of alpha 1(I) (n=67) or alpha 2(I) (n=94). Serine substitutions were the most frequently encountered type of mutation in both chains. Compared with patients with serine substitutions in alpha 2(I) (n=40), patients with serine substitutions in alpha 1(I) (n=42) on average were shorter (median height z-score -6.0 vs -3.4; P=0.005), indicating that alpha 1(I) mutations cause a more severe phenotype. Height correlated with the location of the mutation in the alpha 2(I) chain but not in the alpha 1(I) chain. Patients with mutations affecting the first 120 amino acids at the amino-terminal end of the collagen type I triple helix had blue sclera but did not have dentinogenesis imperfecta. Among patients from different families sharing the same mutation, about 90 and 75% were concordant for dentinogenesis imperfecta and blue sclera, respectively. These data should be useful to predict disease phenotype in newly diagnosed OI patients. European Journal of Human Genetics (2010) 18, 642-647; doi: 10.1038/ejhg.2009.242; published online 20 January 2010