Endocrine Abstracts

JOINT968

Background: Osteogenesis imperfecta (OI), is a rare, generalized connective tissue disorder comprising a heterogeneous group of inherited bone dysplasias with variable phenotypic features and genetic causes. Patients present with low bone mass and bone fragility, substantial growth deficiency and, occasionally, other associated secondary features, including blue sclerae, hearing loss and dentinogenesis imperfecta. The disease is caused mainly by autosomal dominant mutations in type I collagen, or in collagen-related genes with different inheritance patterns. Although there is no clear phenotype – genotype association, the genetic classification of OI helps in detecting specific phenotypic features of the different types of the disease. In the present study, we performed the genetic analysis of 8 new patients with clinical features of osteogenesis imperfecta, in the frame of definitive diagnosis, management and family genetic counselling.

Materials and Methods: Whole exome sequencing was performed and a panel of genes associated with short stature, joint hypermobility, bone fragility or blue sclerae was analysed. The acceptable mean depth of the analysis was 60 and the gene coverage 97%. Any detected pathogenic or likely pathogenic variant was confirmed by Sanger sequencing. The detailed clinical features of the patients were recorded and further analysed based on the type of the genetic change observed.

Results: We found 7 different pathogenic genetic variants in 8 different patients, including frameshift (5/8), missense (2/8) and splicing changes (1/8) in the COL1A1 gene and a missense mutation in the COL1A2. One of the observed genetic variants in exon 46 of the COL1A1 gene has not been previously reported (p.Ala1134Leufs*39). Almost all patients (90%) had severe generalized osteoporosis, mild joint hypermobility, varying degree of multiple fractures and blue sclerae. None of the patient-carriers of frameshift mutations had experienced fractures in utero, during labour or during the newborn period. The patient-carriers of point mutations were diagnosed perinatally. No differences were found regarding the phenotypic variability between the two groups of mutations.

Conclusions: Eight new patients with phenotypic features of osteogenesis imperfecta were genetically diagnosed with pathogenic mutations in COL1A1 and COL1A2 genes, thus, being classified in OI type I, III and IV. Despite the small number of genetically tested patients, it is noteworthy that no phenotypic sign has been reported in utero or during the newborn period for the patients-carriers of frameshift COL1A1 mutations.