Bone Abstracts

Early-onset primary osteoporosis is characterized by low bone mineral density (BMD) and increased tendency to fractures in young people. Studies on rare bone diseases, such as osteogenesis imperfecta (OI), have identified several new genes associated with early-onset skeletal fragility. This study aimed to explore the role of variation in the cartilage-associated protein (CRTAP) gene in early-onset osteoporosis and/or recurrent fractures. We first used homozygosity mapping and Sanger sequencing to screen the 18 genes known to cause OI in a severely affected 11-year-old Iraqi girl, born to consanguineous parents. A disease-causing novel homozygous stop-gain mutation was identified in exon 1 of the CRTAP gene (c.141dupC). The parents of the patient with severe OI, both heterozygous carriers of the CRTAP nonsense mutation, were carefully assessed for BMD and spinal morphology but they did not have evidence of skeletal fragility or a carrier phenotype. To determine whether CRTAP mutations underlie early-onset osteoporosis and recurrent fractures, we screened the CRTAP gene in 96 young subjects with early-onset osteoporosis and/or recurrent fractures using Sanger sequencing. Our analysis did not detect any potential pathogenic variants. In conclusion, we identified a novel duplication in CRTAP causing severe OI but we excluded genetic variants in CRTAP as a common cause for early-onset osteoporosis and recurrent fractures. In line with this, no evidence for skeletal fragility was observed in the heterozygous carriers of the CRTAP stop-gain mutation. These findings suggest that CRTAP mutations result only in the previously described OI type III phenotype and do not underlie milder forms of early-onset osteoporosis.