{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:15:33Z","timestamp":1790280933607,"version":"4.1.0"},"reference-count":38,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T00:00:00Z","timestamp":1642032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/genes13010137","type":"journal-article","created":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T10:57:37Z","timestamp":1642071457000},"page":"137","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Clinical and Genetic Characteristics of COL2A1-Associated Skeletal Dysplasias in 60 Russian Patients: Part I"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2672-6294","authenticated-orcid":false,"given":"Tatyana","family":"Markova","sequence":"first","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye st., 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7651-8485","authenticated-orcid":false,"given":"Vladimir","family":"Kenis","sequence":"additional","affiliation":[{"name":"H. Turner National Medical Research Center for \u0421hildren\u2019s Orthopedics and Trauma Surgery, Parkovaya 64\u201368, 196603 Saint-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgeniy","family":"Melchenko","sequence":"additional","affiliation":[{"name":"H. Turner National Medical Research Center for \u0421hildren\u2019s Orthopedics and Trauma Surgery, Parkovaya 64\u201368, 196603 Saint-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5863-3543","authenticated-orcid":false,"given":"Darya","family":"Osipova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye st., 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana","family":"Nagornova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye st., 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8831-1844","authenticated-orcid":false,"given":"Anna","family":"Orlova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye st., 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Zakharova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye st., 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Dadali","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye st., 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Kutsev","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye st., 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,13]]},"reference":[{"key":"ref_1","unstructured":"(2021, November 22). Type II Collagen Disorders Overview\u2014GeneReviews\u00ae\u2014NCBI Bookshelf, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK540447\/."},{"key":"ref_2","first-page":"56","article-title":"The type II collagenopathies: A spectrum of chondrodysplasias","volume":"153","author":"Spranger","year":"1994","journal-title":"Eur. J. Pediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/humu.20179","article-title":"The phenotypic spectrum of COL2A1 mutations","volume":"26","author":"Nishimura","year":"2005","journal-title":"Hum. Mutat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1097\/MOP.0b013e32832185c5","article-title":"Genetic and orthopedic aspects of collagen disorders","volume":"21","author":"Carter","year":"2009","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_5","first-page":"992","article-title":"The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype","volume":"24","author":"Dumont","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/humu.22915","article-title":"Mutation Update for COL2A1 Gene Variants Associated with Type II Collagenopathies","volume":"37","author":"Sarrabay","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1002\/ajmg.a.61366","article-title":"Nosology and classification of genetic skeletal disorders: 2019 revision","volume":"179","author":"Mortier","year":"2019","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1148\/rg.2021200075","article-title":"Radiologic features of type II and type XI collagenopathies","volume":"41","author":"Handa","year":"2021","journal-title":"Radiographics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1007\/s11999-011-1850-x","article-title":"Two novel COL2A1 mutations associated with a Legg-Calv\u00e9-Perthes disease-like presentation","volume":"469","author":"Kannu","year":"2011","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1002\/ajmg.a.34056","article-title":"Avascular necrosis of the femoral head due to a novel C propeptide mutation in COL2A1","volume":"155A","author":"Kannu","year":"2011","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/ajmg.a.30955","article-title":"Stickler syndrome: Clinical characteristics and diagnostic criteria","volume":"138A","author":"Rose","year":"2005","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1002\/art.27354","article-title":"Premature arthritis is a distinct type II collagen phenotype","volume":"62","author":"Kannu","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1002\/ajmg.a.36922","article-title":"A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphyseal dysplasia congenita or a related phenotype","volume":"167A","author":"Terhal","year":"2015","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1242\/jcs.01731","article-title":"Procollagen trafficking, processing and fibrillogenesis","volume":"118","author":"Canty","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1111\/cge.13680","article-title":"Integrated analysis of COL2A1 variant data and classification of type II collagenopathies","volume":"97","author":"Zhang","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.joca.2010.03.001","article-title":"Bone Morphogenetic Proteins and articular cartilage: To serve and protect or a wolf in sheep clothing\u2019s?","volume":"18","year":"2010","journal-title":"Osteoarthr. Cartil."},{"key":"ref_17","unstructured":"(2021, December 02). HGMD\u00ae Professional Version 2021. Available online: http:\/\/www.hgmd.cf.ac.uk\/ac\/index.php."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"235","DOI":"10.2147\/TACG.S197205","article-title":"COL2A1 Gene Mutations: Mechanisms of Spondyloepiphyseal Dysplasia Congenita","volume":"12","author":"Nenna","year":"2019","journal-title":"Appl. Clin. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1002\/ajmg.c.31332","article-title":"Mutation-based growth charts for SEDC and other COL2A1 related dysplasias","volume":"160C","author":"Terhal","year":"2012","journal-title":"Am. J. Med. Genet. C. Semin. Med. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1002\/humu.9497","article-title":"Missense and silent mutations in COL2A1 result in Stickler syndrome but via different molecular mechanisms","volume":"28","author":"Richards","year":"2007","journal-title":"Hum. Mutat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1038\/ejhg.2010.23","article-title":"Stickler syndrome caused by COL2A1 mutations: Genotype\u2013phenotype correlation in a series of 100 patients","volume":"18","author":"Hoornaert","year":"2010","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/(SICI)1096-8628(19990716)85:2<105::AID-AJMG2>3.0.CO;2-Z","article-title":"Small deletions in the type II collagen triple helix produce kniest dysplasia","volume":"85","author":"Wilkin","year":"1999","journal-title":"Am. J. Med. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1111\/cge.12466","article-title":"Autosomal recessive mutations in the COL2A1 gene cause severe spondyloepiphyseal dysplasia","volume":"87","author":"Tham","year":"2015","journal-title":"Clin. Genet."},{"key":"ref_24","first-page":"263","article-title":"Confirmation of autosomal recessive inheritance of COL2A1 mutations in spondyloepiphyseal dysplasia congenita: Lessons for genetic counseling","volume":"170A","author":"Baujat","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mrrev.2016.02.003","article-title":"Molecular genetics of the COL2A1-related disorders","volume":"768","author":"Deng","year":"2016","journal-title":"Mutat. Res. Rev. Mutat. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1002\/ajmg.a.61414","article-title":"Biallelic variants p.Arg1133Cys and p.Arg1379Cys in COL2A1: Further delineation of phenotypic spectrum of recessive Type 2 collagenopathies","volume":"182","author":"Girisha","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chen, J., Ma, X., Zhou, Y., Li, G., and Guo, Q. (2017). Recurrent c.G1636A (p.G546S) mutation of COL2A1 in a Chinese family with skeletal dysplasia and different metaphyseal changes: A case report. BMC Pediatr., 17.","DOI":"10.1186\/s12887-017-0930-9"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1002\/jor.1100140506","article-title":"Alternative splicing of exon 12 of the COL2A1 gene interrupts the triple helix of type-II collagen in the Kniest form of spondyloepiphyseal dysplasia","volume":"14","author":"Chen","year":"1996","journal-title":"J. Orthop. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1002\/humu.22839","article-title":"Novel COL2A1 variant (c.619G>A, p.Gly207Arg) manifesting as a phenotype similar to progressive pseudorheumatoid dysplasia and spondyloepiphyseal dysplasia, Stanescu type","volume":"36","author":"Jurgens","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.joca.2019.12.011","article-title":"Skeletal deterioration in COL2A1-related spondyloepiphyseal dysplasia occurs prior to osteoarthritis","volume":"28","author":"Rolvien","year":"2020","journal-title":"Osteoarthr. Cartil."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2715","DOI":"10.1002\/ajmg.a.61817","article-title":"Spondyloepiphyseal dysplasia type Stanescu: Expanding the clinical and molecular spectrum of a very rare type II collagenopathy","volume":"182","author":"Travessa","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1002\/ajmg.a.30881","article-title":"Novel amino acid substitution in the Y-position of collagen type II causes spondyloepimetaphyseal dysplasia congenita","volume":"137A","author":"Wozniak","year":"2005","journal-title":"Am. J. Med. Genet. A."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1136\/jmg.2005.035717","article-title":"The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene","volume":"43","author":"Hoornaert","year":"2006","journal-title":"J. Med. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Choi, S.I., Woo, S.J., Oh, B.L., Han, J., Lim, H.T., Lee, B.J., Joo, K., Park, J.Y., Jang, J.H., and So, M.K. (2021). Genetic Characteristics and Phenotype of Korean Patients with Stickler Syndrome: A Korean Multicenter Analysis Report No. 1. Genes, 12.","DOI":"10.3390\/genes12101578"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1136\/jmg.33.8.649","article-title":"The deletion of six amino acids at the C-terminus of the alpha 1 (II) chain causes overmodification of type II and type XI collagen: Further evidence for the association between small deletions in COL2A1 and Kniest dysplasia","volume":"33","author":"Winterpacht","year":"1996","journal-title":"J. Med. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bruni, V., Spoleti, C.B., La Barbera, A., Dattilo, V., Colao, E., Votino, C., Bellacchio, E., Perrotti, N., Giglio, S., and Iuliano, R. (2021). A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions. Genes, 12.","DOI":"10.3390\/genes12091395"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1111\/opo.12682","article-title":"A novel deep intronic COL2A1 mutation in a family with early-onset high myopia\/ocular-only Stickler syndrome","volume":"40","author":"Sun","year":"2020","journal-title":"Ophthalmic Physiol. Opt."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/1\/137\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:14:59Z","timestamp":1760364899000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/1\/137"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,13]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["genes13010137"],"URL":"https:\/\/doi.org\/10.3390\/genes13010137","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,13]]}}}