{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T22:51:04Z","timestamp":1773269464014,"version":"3.50.1"},"reference-count":28,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T00:00:00Z","timestamp":1631232000000},"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>Achondrogenesis type II (ACG2) is a lethal skeletal dysplasia caused by dominant pathogenic variants in COL2A1. Most of the variants found in patients with ACG2 affect the glycine residue included in the Gly-X-Y tripeptide repeat that characterizes the type II collagen helix. In this study, we reported a case of a novel splicing variant of COL2A1 in a fetus with ACG2. An NGS analysis of fetal DNA revealed a heterozygous variant c.1267-2_1269del located in intron 20\/exon 21. The variant occurred de novo since it was not detected in DNA from the blood samples of parents. We generated an appropriate minigene construct to study the effect of the variant detected. The minigene expression resulted in the synthesis of a COL2A1 messenger RNA lacking exon 21, which generated a predicted in-frame deleted protein. Usually, in-frame deletion variants of COL2A1 cause a phenotype such as Kniest dysplasia, which is milder than ACG2. Therefore, we propose that the size and position of an in-frame deletion in COL2A1 may be relevant in determining the phenotype of skeletal dysplasia.<\/jats:p>","DOI":"10.3390\/genes12091395","type":"journal-article","created":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T10:31:34Z","timestamp":1631269894000},"page":"1395","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4958-9536","authenticated-orcid":false,"given":"Valentina","family":"Bruni","sequence":"first","affiliation":[{"name":"Medical Genetics Unit, Department of Health Sciences, University \u201cMagna Graecia\u201d of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina Barbara","family":"Spoleti","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Department of Health Sciences, University \u201cMagna Graecia\u201d of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0606-8404","authenticated-orcid":false,"given":"Andrea","family":"La Barbera","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences \u201cMario Serio\u201d, University of Florence, 50121 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Dattilo","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Department of Health Sciences, University \u201cMagna Graecia\u201d of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5451-593X","authenticated-orcid":false,"given":"Emma","family":"Colao","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Department of Health Sciences, University \u201cMagna Graecia\u201d of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmela","family":"Votino","sequence":"additional","affiliation":[{"name":"Fetal Medicine Unit, ASL Bari, 70012 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuele","family":"Bellacchio","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicola","family":"Perrotti","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Department of Health Sciences, University \u201cMagna Graecia\u201d of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3954-326X","authenticated-orcid":false,"given":"Sabrina","family":"Giglio","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, 09124 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8524-7402","authenticated-orcid":false,"given":"Rodolfo","family":"Iuliano","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Department of Health Sciences, University \u201cMagna Graecia\u201d of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/ajmg.1320100411","article-title":"Achondrogenesis: A review with special consideration of achondrogenesis type II (Langer-Saldino)","volume":"10","author":"Chen","year":"1981","journal-title":"Am. J. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1148\/92.2.285","article-title":"Thanatophoric dwarfism: A condition confused with achondroplasia in the neonate, with brief comments on achondrogenesis and homozygous achondroplasia","volume":"92","author":"Langer","year":"1969","journal-title":"Radiology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"185","DOI":"10.2214\/ajr.112.1.185","article-title":"Lethal short-limbed dwarfism: Achondrogenesis and thanatophoric dwarfism","volume":"112","author":"Saldino","year":"1971","journal-title":"Am. J. Roentgen. Radium Ther. Nucl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1002\/ajmg.a.33909","article-title":"Nosology and classification of genetic skeletal disorders: 2010 revision","volume":"155","author":"Warman","year":"2011","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_5","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":"167","author":"Terhal","year":"2015","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S0959-437X(96)80006-2","article-title":"Bone dysplasias in man: Molecular insights","volume":"6","author":"Francomano","year":"1996","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"2803","DOI":"10.1073\/pnas.84.9.2803","article-title":"Tissue-specific expression of the human type II collagen gene in mice","volume":"84","author":"Bygrave","year":"1987","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1038\/ejhg.2015.250","article-title":"The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype","volume":"24","author":"Dumont","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Huang, L., Chen, C., Wang, Z., Sun, L., Li, S., Zhang, T., Luo, X., and Ding, X. (2020). Mutation Spectrum and De Novo Mutation Analysis in Stickler Syndrome Patients with High Myopia or Retinal Detachment. Genes, 11.","DOI":"10.3390\/genes11080882"},{"key":"ref_12","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_13","doi-asserted-by":"crossref","first-page":"4761","DOI":"10.1074\/jbc.273.8.4761","article-title":"Structurally abnormal type II collagen in a severe form of Kniest dysplasia caused by an exon 24 skipping mutation","volume":"273","author":"Weis","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1093\/bioinformatics\/btv195","article-title":"PROVEAN web server: A tool to predict the functional effect of amino acid substitutions and indels","volume":"31","author":"Choi","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1038\/eye.2008.34","article-title":"The influence of pre-mRNA splicing on phenotypic modification in Stickler\u2019s syndrome and other type II collagenopathies","volume":"22","author":"Richards","year":"2008","journal-title":"Eye"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/j.addr.2003.08.002","article-title":"Collagens-structure, function, and biosynthesis","volume":"55","author":"Gelse","year":"2003","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1002\/(SICI)1096-8628(20000515)92:2<95::AID-AJMG3>3.0.CO;2-9","article-title":"Widely Distributed Mutations in the COL2A1 Gene Produce Achondrogenesis Type II\/Hypochondrogenesis","volume":"92","author":"Cohn","year":"2000","journal-title":"Am. J. Med. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/ng0493-323","article-title":"Kniest and Stickler dysplasia phenotypes caused by collagen type II gene (COL2A1) defect","volume":"3","author":"Winterpacht","year":"1993","journal-title":"Nat. Genet."},{"key":"ref_20","first-page":"1128","article-title":"Expression, in cartilage, of a 7-amino-acid deletion in type II collagen from two unrelated individuals with Kniest dysplasia","volume":"55","author":"Bogaert","year":"1994","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1006\/abbi.1998.0745","article-title":"Incorporation of structurally defective type II collagen into cartilage matrix in kniest chondrodysplasia","volume":"355","author":"Fernandes","year":"1998","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.3109\/14767058.2010.545903","article-title":"Prenatal diagnosis of Kniest dysplasia with three-dimensional helical computed tomography","volume":"24","author":"Wada","year":"2011","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1002\/(SICI)1096-8628(19970303)69:1<79::AID-AJMG15>3.0.CO;2-L","article-title":"Kniest dysplasia: Dr. W. Kniest, his patient, the molecular defect","volume":"69","author":"Spranger","year":"1997","journal-title":"Am. J. Med. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1093\/hmg\/3.10.1891","article-title":"Alternative splicing as the result of a type II procollagen gene (COL2A1) mutation in a patient with Kniest dysplasia","volume":"3","author":"Winterpacht","year":"1994","journal-title":"Hum. Mol. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1136\/jmg.37.4.263","article-title":"Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype correlation in patients with a lethal type II collagen disorder","volume":"37","author":"Mortier","year":"2000","journal-title":"J. Med. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1126\/science.2543071","article-title":"(Identification of the molecular defect in a family with spondyloepiphyseal dysplasia","volume":"244","author":"Lee","year":"1989","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7640","DOI":"10.1073\/pnas.88.17.7640","article-title":"Expression of a partially deleted gene of human type II procollagen (COL2A1) in transgenic mice produces a chondrodysplasia","volume":"88","author":"Vandenberg","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1083\/jcb.118.1.203","article-title":"Chondrodysplasia in transgenic mice harboring a 15-amino acid deletion in the triple helical domain of pro \u03b1 1(II) collagen chain","volume":"118","author":"Garofalo","year":"1992","journal-title":"J. Cell Biol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/9\/1395\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:00:03Z","timestamp":1760166003000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/9\/1395"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,10]]},"references-count":28,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["genes12091395"],"URL":"https:\/\/doi.org\/10.3390\/genes12091395","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,10]]}}}