{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T15:04:29Z","timestamp":1783091069086,"version":"3.54.6"},"reference-count":9,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2019,9,30]],"date-time":"2019-09-30T00:00:00Z","timestamp":1569801600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>With increased access to genetic testing, variants of uncertain significance (VUS) where pathogenicity is uncertain are being increasingly identified. More than 85% Osteogenesis Imperfecta (OI) patients have pathogenic variants in <jats:italic>COL1A1\/A2<\/jats:italic>. However, when a VUS is identified, there are no pathways in place for determining significance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>Define a diagnostic pathway to confirm pathogenicity, providing patients with definitive genetic diagnosis, accurate recurrence risks, and prenatal testing options.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Functional studies on collagen secretion from cultured patient fibroblasts combined with detailed phenotyping and segregation family studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrate data from a family with a VUS identified in type I collagen.<\/jats:p><\/jats:sec><jats:sec><jats:title>Family\u20101<\/jats:title><jats:p>Six\u2010year\u2010old boy with failure\u2010to\u2010gain weight, talipes, fractures, on and off treatment with Pamidronate as diagnosis of OI uncertain. Transiliac bone biopsy at 2 years of age demonstrated active new bone formation within periosteum; bone cortices were normal thickness but increased porosity. Trabecular bone showed features of advanced osteoporosis. Genetic testing identified a de novo<jats:italic> COL1A1<\/jats:italic> c.206_208delTGT, p.Leu69del variant. Sibling with similar phenotype but no fractures as yet, tested positive for variant raising concerns regarding her diagnosis, and management.<\/jats:p><jats:p>Results from three independent experiments (cell immunofluorescence, collagen secretion assay by Western Blot, and unbiased proteomics) from cultured patient fibroblasts demonstrate COL1A1 c.206_208delTGT, p.Leu69del variant causing a substantial defect to collagen extracellular matrix assembly confirming variant pathogenicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Access to genetic testing in OI is increasing as advances in genetic technologies decreases cost; a clinical diagnostic pathway needs to be implemented for managing variants identified by such testing.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.912","type":"journal-article","created":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T05:35:00Z","timestamp":1569908100000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Developing pathways to clarify pathogenicity of unclassified variants in Osteogenesis Imperfecta genetic analysis"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1488-3695","authenticated-orcid":false,"given":"Meena","family":"Balasubramanian","sequence":"first","affiliation":[{"name":"Highly Specialised Severe, Complex &amp; Atypical OI Service Sheffield Children\u2019s NHS Foundation Trust Sheffield UK"},{"name":"Sheffield Clinical Genetics Service Sheffield Children's NHS Foundation Trust Sheffield UK"},{"name":"Academic Unit of Child Health University of Sheffield Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Hobson","sequence":"additional","affiliation":[{"name":"Yorkshire Clinical Genetics Service Chapel Allerton Hospital Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mars","family":"Skae","sequence":"additional","affiliation":[{"name":"Department of Paediatric Endocrinology Royal Manchester Children\u2019s Hospital Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"McCaughey","sequence":"additional","affiliation":[{"name":"School of Biochemistry, Faculty of Life Sciences University of Bristol Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Stephens","sequence":"additional","affiliation":[{"name":"School of Biochemistry, Faculty of Life Sciences University of Bristol Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,9,30]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.106.3.999"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/1047-8477(90)90110-x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(15)00728-x"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2017.02.004"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-100913-013002"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.04.062"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.28401"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.212308"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)61036-1"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.912","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mgg3.912","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.912","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T18:40:32Z","timestamp":1692643232000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.912"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,30]]},"references-count":9,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["10.1002\/mgg3.912"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.912","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"value":"2324-9269","type":"print"},{"value":"2324-9269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,30]]},"assertion":[{"value":"2019-01-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-07-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e912"}}