{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T16:39:25Z","timestamp":1770914365993,"version":"3.50.1"},"reference-count":22,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T00:00:00Z","timestamp":1668988800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/W01761X\/1"],"award-info":[{"award-number":["MR\/W01761X\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["203141\/Z\/16\/Z"],"award-info":[{"award-number":["203141\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013373","name":"NIHR Biomedical Research Centre, Oxford","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100013373","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2022,10,14]]},"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:p>Many genetic testing methodologies are biased towards picking up structural variants (SVs) that alter copy number. Copy-neutral rearrangements such as inversions are therefore likely to suffer from underascertainment. In this study, manual review prompted by a virtual multidisciplinary team meeting and subsequent bioinformatic prioritisation of data from the 100K Genomes Project was performed across 43 genes linked to well-characterised skeletal disorders. Ten individuals from three independent families were found to harbour diagnostic inversions. In two families, inverted segments of 1.2\/14.8\u2009Mb unequivocally disrupted <jats:italic>GLI3<\/jats:italic> and segregated with skeletal features consistent with Greig cephalopolysyndactyly syndrome. For one family, phenotypic blending was due to the opposing breakpoint lying ~45\u2009kb from <jats:italic>HOXA13<\/jats:italic>. In the third family, long suspected to have Marfan syndrome, a 2.0\u2009Mb inversion disrupting <jats:italic>FBN1<\/jats:italic> was identified. These findings resolved lengthy diagnostic odysseys of 9\u201320 years and highlight the importance of direct interaction between clinicians and data-analysts. These exemplars of a rare mutational class inform future SV prioritisation strategies within the NHS Genomic Medicine Service and similar genome sequencing initiatives. In over 30 years since these two disease-gene associations were identified, large inversions have yet to be described and so our results extend the mutational spectra linked to these conditions.<\/jats:p>","DOI":"10.1136\/jmg-2022-108753","type":"journal-article","created":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T13:20:26Z","timestamp":1669036826000},"page":"505-510","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Conclusion of diagnostic odysseys due to inversions disrupting <i>GLI3<\/i> and <i>FBN1<\/i>"],"prefix":"10.1136","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7334-0602","authenticated-orcid":false,"given":"Alistair T","family":"Pagnamenta","sequence":"first","affiliation":[{"name":"Wellcome Centre for Human Genetics, University of Oxford, Oxford, Oxfordshire, UK"},{"name":"Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, Oxfordshire, 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