Сlinical and genetic characteristics of skeletal cyliopathies – short-rib thoracic dysplasia

Abstract

BACKGROUND: Ciliopathies include the large group of hereditary diseases caused by mutations in the genes encoding primary cilia components. The largest type of skeletal ciliopathies is short-rib thoracic dysplasia. AIM: This study describes the clinical and genetic characteristics of Russian patients with STRD with or without polydactyly caused by mutations in the genes DYNC2H1, DYNC2I2, IFT80, and IFT140. MATERIALS AND METHODS: A comprehensive examination of 10 unrelated children aged from 9 days to 9 years, with phenotypic signs of short-rib thoracic dysplasia with or without polydactyly, was conducted. The diagnosis was confirmed using genealogical analysis, clinical examination, neurological examination, radiography, and targeted sequencing of a panel consisting of 166 genes responsible for the development of inherited skeletal pathology. RESULTS: As a result of the molecular genetic analysis, four short-rib thoracic dysplasia genetic variants were identified. Seven patients were diagnosed with short-rib thoracic dysplasia type 3, and three unique patients were diagnosed with types 11, 2, and 9 due to mutations in the DYNC2H1 and DYNC2I2, IFT80, and IFT140 genes, respectively. From the 14 detected variants, six were identified for the first time. As in the previously described patient samples, in the analyzed sample, more than half of the cases were due to a mutation in the DYNC2H1 gene, which is responsible for the SRTD type 3. The differences in the severity of clinical manifestations and the disease course in patients with mutations in certain regions of the gene, which have a different effect on its protein product function, have been shown. CONCLUSIONS: The results of this molecular genetic study broaden the spectrum of mutations in the DYNC2H1, DYNC212, and IFT140 genes causing short-rib thoracic dysplasia and confirm the usefulness of the whole-exome sequencing as the most informative method for identifying mutations of the genetically heterogeneous short-rib thoracic dysplasia group.