Identification of new genes and investigation of related proteins in rare skeletal dysplasias

INTRODUCTION: Skeletal dysplasias are a large group of disorders that mostly manifest with disproportionate short stature, in which bone and/or cartilage tissue is affected. To date, more than 450 skeletal dysplasia syndromes have been identified and 437 different genes related to these syndromes have been reported. The genetic cause of some skeletal dysplasia is still unclear. Skeletal dysplasias are a group of clinically and genetically heterogeneous disorders. While mutations in different genes can lead to similar phenotypes, mutations in the same gene can cause different phenotypes. Clinical diagnosis is therefore difficult and requires experience. Sequencing of the whole genome or a part of it has become possible with recently available sequencing technologies. In cases where there are overlapping findings, such as with skeletal dysplasias, this method is able to identify the molecular basis of these diseases. AIM: In our study, we aimed to investigate genes related to skeletal dysplasia syndromes using whole exome sequencing. We focused on patients with skeletal dysplasia that could not be diagnosed clinically or molecularly to identify new candidate genes and to contribute to phenotypic expansion, by identifying new findings in patients with mutations associated with known syndromes. METHOD AND RESULTS: 87 patients from 68 families were included in our study. Our study group did not include patients diagnosed with osteogenesis imperfecta and decreased bone mineralization, primordial dwarfism and slender bone dysplasia group, craniosynostosis syndromes, ectrodactylic syndromes, and fanconia anemia. Clinical diagnosis was confirmed in 46 families (67%) with the whole exome sequencing method. The new candidate gene was found in 7 families (10%). In 15 families we could not explain the molecular cause of the disease. DISCUSSION AND CONCLUSION: In this study, the success of diagnosing whole exome sequencing in rare skeletal dysplasia syndromes was found to be 67%, which is higher than reported in the literature. The advanced diagnostic success rates in our clinic, which is a reference center for skeletal dysplasia in Turkey, is a result of having access to a large patient cohort, selecting relevant patients carefully for this specific study based on abundant clinical and radiological data and implementing appropriate correlation studies between the clinical data sets and patients' genetic information.