Bone Abstracts

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity to fracture. Over 90% of patients with OI have a mutation in COL1A1/COL1A2, which shows an autosomal dominant pattern of inheritance. Several other genes are associated with the autosomal recessive forms of OI. In-depth phenotyping and in particular, studies involving manifestations in the skin connective tissue have not previously been undertaken in OI. With increasing use of genomics in clinical practice, it becomes even more important to have extensive phenotyping data in order to make meaningful interpretation of variants identified through these studies.

As part of the rare diseases in bone, joints and/or blood vessels (RUDY) study, in collaboration with the NIHR Rare Diseases Translational Research Collaboration, we undertook a national study of skin biopsies in patients with OI. The plan was to perform ultrastructural examination and phenotype-based assays of the skin connective tissue in patients with OI; to enable use of results in the diagnostic work-up of OI.

From a previous pilot study done in Sheffield, we know that there are important indicators on electron microscopy of identifying a pathogenic mutation in COL1A1/A2 (Balasubramanian et al. Clin Dysmorphol 2014). As part of this larger study, we studied the manifestations in the skin connective tissue and undertook in-depth clinical and molecular phenotyping of patients with OI. This in combination with phenotype-based assays on cultured fibroblasts have provided more insight into the pathways to direct gene testing and reinforced the need for accurate phenotyping in conjunction with genomic analyses.

Disclosure: The authors declared no competing interests.