Genetic analysis of osteogenesis imperfecta in the Palestinian population : molecular screening of 49 affected families

Background : Osteogenesis imperfecta (OI) is a heterogeneous hereditary connective tissue disorder clinically hallmarked by increased susceptibility to bone fractures. Methods : We analyzed a cohort of 77 diagnosed OI patients from 49 unrelated Palestinian families. Next-generation sequencing technology was used to screen a panel of known OI genes. Results : In 41 probands, we identified 28 different disease-causing variants of 9 different known OI genes. Eleven of the variants are novel. Ten of the 28 variants are located in COL1A1, five in COL1A2, three in BMP1, three in FKBP10, two in TMEM38B, two in P3H1, and one each in CRTAP, SERPINF1, and SERPINH1. The absence of disease-causing variants in the remaining eight probands suggests further genetic heterogeneity in OI. In general, most OI patients (90%) harbor mainly variants in type I collagen resulting in an autosomal dominant inheritance pattern. However, in our cohort almost 61% (25/41) were affected with autosomal recessive OI. Moreover, we document a 21-kb genomic deletion in the TMEM38B gene identified in 29% (12/41) of the tested probands, making it the most frequent OI-causing variant in the Palestinian population. Conclusion : This is the first genetic screening of an OI cohort from the Palestinian population. Our data are important for genetic counseling of OI patients and families in highly consanguineous populations

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 α1 or the α2 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 α1(I) (n=67) or α2(I) (n=94). Serine substitutions were the most frequently encountered type of mutation in both chains. Compared with patients with serine substitutions in α2(I) (n=40), patients with serine substitutions in α1(I) (n=42) on average were shorter (median height z-score −6.0 vs −3.4; P=0.005), indicating that α1(I) mutations cause a more severe phenotype. Height correlated with the location of the mutation in the α2(I) chain but not in the α1(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