Abstract
The significant variability in the clinical manifestations of COL2A1-associated skeletal dysplasias makes it necessary to conduct a clinical and genetic analysis of individual nosological variants, which will contribute to improving our understanding of the pathogenetic mechanisms and prognosis. We presented the clinical and genetic characteristics of 60 Russian pediatric patients with type II collagenopathies caused by previously described and newly identified variants in the COL2A1 gene. Diagnosis confirmation was carried out by new generation sequencing of the target panel with subsequent validation of the identified variants using automated Sanger sequencing. It has been shown that clinical forms of spondyloepiphyseal dysplasias predominate in childhood, both with more severe clinical manifestations (58%) and with unusual phenotypes of mild forms with normal growth (25%). However, Stickler syndrome, type I was less common (17%). In the COL2A1 gene, 28 novel variants were identified, and a total of 63% of the variants were found in the triple helix region resulted in glycine substitution in Gly-XY repeats, which were identified in patients with clinical manifestations of congenital spondyloepiphyseal dysplasia with varying severity, and were not found in Stickler syndrome, type I and Kniest dysplasia. In the C-propeptide region, five novel variants leading to the development of unusual phenotypes of spondyloepiphyseal dysplasia have been identified.
Highlights
COL2A1-associated skeletal dysplasias are a large group of genetically heterogeneous diseases with an autosomal dominant type of inheritance caused by pathogenic variants in the COL2A1 gene (OMIM:120140) [1]
Based on the clinical and genetic characteristics of 60 Russian pediatric patients with variants in the COL2A1 gene, an etiological cause and a range of typical and atypical phenotypes have been established, which are important in the formation of approaches to the type II collagenopathies diagnosis
It was shown that clinical forms of Spondyloepiphyseal dysplasia (SED) predominate in childhood, both with more severe clinical manifestations: SEDC, spondyloepimetaphyseal dysplasia (SEMD), and Kniest dysplasia (KD) (58%), and with unusual mild forms of SED phenotypes with normal growth (25%), accompanied by early osteoarthritis with a rheumatoid-like course or hiding under the guise of Legg
Summary
COL2A1-associated skeletal dysplasias are a large group of genetically heterogeneous diseases with an autosomal dominant type of inheritance caused by pathogenic variants in the COL2A1 gene (OMIM:120140) [1]. The main clinical feature of this group is dwarfism, characterized by a shortening of the trunk [2]. Some patients have extra-skeletal symptoms, including myopia, vitreous abnormalities, retinal detachment, cataracts, glaucoma, sensorineural hearing loss, as well as orofacial anomalies-midface hypoplasia, micrognathia, cleft palate, or Pierre Robin sequence [3,4,5,6]. Patients with overlapping phenotypes have been described. The clinical manifestations of this area of diseases represent a single “clinical continuum”, united in the group of “type II collagenopathies”, indicated in the international nosology and classification of genetic skeletal disorders [7]
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