{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T06:24:44Z","timestamp":1787120684776,"version":"build-2736575974"},"reference-count":33,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":229,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Osteogenesis imperfecta (OI) is a clinical and genetic disorder characterised by bone fragility, growth deficiency and skeletal deformity. Ninety per cent of OI cases are attributable to autosomal dominant variants in the\n                      <jats:italic>COL1A1<\/jats:italic>\n                      and\n                      <jats:italic>COL1A2<\/jats:italic>\n                      genes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Candidate variants were identified and verified through trio whole\u2010exome sequencing (trio\u2010WES), copy number variation sequencing (CNV\u2010seq) and Sanger sequencing. Minigene splicing assays were performed in HeLa and HEK293T cells with pcDNA3.1 and pcMINI\u2010C vectors to investigate the function of the candidate variants. A systematic review of\n                      <jats:italic>COL1A1<\/jats:italic>\n                      splicing variants and the corresponding genotype\u2013phenotype spectrum was performed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Trio\u2010WES revealed a novel heterozygous variant in the C\u2010terminal region of the\n                      <jats:italic>COL1A1<\/jats:italic>\n                      gene: NM_000088.4:c.3423+5G&gt;A. Sanger sequencing confirmed the variant in both the proband (II\u20102) and her foetus (III\u20101) who were clinically suspected of having OI. The c.3423+5G&gt;A variant causes complete skipping of Exon 46, as demonstrated by a minigene splicing assay. We retrieved 419\n                      <jats:italic>COL1A1<\/jats:italic>\n                      splicing variants from PubMed, excluded 15 without phenotypic data and 2 linked to Ehlers\u2013Danlos syndrome and stratified the remaining 402 variants into three types on the basis of splice site location: (1) Variants at canonical splicing sites (77.8%, 313\/402) mostly cause mild phenotypes, whereas a minority may be severe. (2) Intron variants in other locations, such as splice region variants (17.9%, 72\/402), usually cause mild clinical phenotypes, and deep intronic splice variants (0.4%, 2\/402) that may result in severe phenotypes. (3) Other variants (3.7%, 15\/402), such as exon variants or fragment loss, are extremely rare. We also preliminarily discuss the mechanisms underlying phenotypic variability and the characteristics of C\u2010terminal variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This intron variant in\n                      <jats:italic>COL1A1<\/jats:italic>\n                      was classified as likely pathogenic and was confirmed to disrupt\n                      <jats:italic>COL1A1<\/jats:italic>\n                      expression. The summary analysis results also revealed a correlation among splicing variants, C\u2010terminal region variants and disease, suggesting that variant location provides a useful framework for prognosis prediction.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/humu\/2249583","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T05:29:33Z","timestamp":1787117373000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Splice Variant in the\n                    <i>COL1A1<\/i>\n                    Gene Leads to Exon 46 Skipping and Osteogenesis Imperfecta"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5460-973X","authenticated-orcid":false,"given":"Yujun","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huibing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ailan","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanfei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7936-8777","authenticated-orcid":false,"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5406-0506","authenticated-orcid":false,"given":"Bei","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"e_1_2_15_1_2","doi-asserted-by":"publisher","DOI":"10.3390\/polym13162642"},{"key":"e_1_2_15_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diff.2024.100757"},{"key":"e_1_2_15_3_2","volume-title":"COL1A1 Collagen Type I Alpha 1 Chain [Homo sapiens (human)]","author":"NCBI Gene","year":"2026"},{"key":"e_1_2_15_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22812"},{"key":"e_1_2_15_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2017.06.001"},{"key":"e_1_2_15_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.14"},{"key":"e_1_2_15_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-021-01274-y"},{"key":"e_1_2_15_8_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.16.2.101"},{"key":"e_1_2_15_9_2","volume-title":"An Online Catalog of Human Genes and Genetic Disorders","author":"Online Mendelian Inheritance in Man (OMIM)","year":"2026"},{"key":"e_1_2_15_10_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2019.00979"},{"key":"e_1_2_15_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-019-0686-8"},{"key":"e_1_2_15_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2018.42"},{"key":"e_1_2_15_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2023.100866"},{"key":"e_1_2_15_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23626"},{"key":"e_1_2_15_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23718"},{"key":"e_1_2_15_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2021.116293"},{"key":"e_1_2_15_17_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.816078"},{"key":"e_1_2_15_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2023.116683"},{"key":"e_1_2_15_19_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40246-025-00816-8"},{"key":"e_1_2_15_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13353-018-0444-7"},{"key":"e_1_2_15_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.12.015"},{"key":"e_1_2_15_22_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-023-02547-z"},{"key":"e_1_2_15_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.52"},{"key":"e_1_2_15_24_2","volume-title":"Global Variant Database and Gene Centered Collection","author":"Leiden Open Variation Database (LOVD)","year":"2025"},{"key":"e_1_2_15_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22677"},{"key":"e_1_2_15_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2019.04.018"},{"key":"e_1_2_15_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12783"},{"key":"e_1_2_15_28_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117161"},{"key":"e_1_2_15_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.09.012"},{"key":"e_1_2_15_30_2","first-page":"670","article-title":"Phenotypic Heterogeneity in Osteogenesis Imperfecta: The Mildly Affected Mother of a Proband With a Lethal Variant Has the Same Mutation Substituting Cysteine for Alpha 1-Glycine 904 in a Type I Procollagen Gene (COL1A1)","volume":"47","author":"Constantinou C. 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