{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T07:32:51Z","timestamp":1780471971861,"version":"3.54.1"},"reference-count":50,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2023,10,9]],"date-time":"2023-10-09T00:00:00Z","timestamp":1696809600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["UK10K"],"award-info":[{"award-number":["UK10K"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WCMA_P43883"],"award-info":[{"award-number":["WCMA_P43883"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT091310"],"award-info":[{"award-number":["WT091310"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"NIHR","doi-asserted-by":"crossref","award":["RG65966"],"award-info":[{"award-number":["RG65966"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2023,9,18]]},"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The Ehlers-Danlos syndromes (EDS) are heritable disorders of connective tissue (HDCT), reclassified in the 2017 nosology into 13 subtypes. The genetic basis for hypermobile Ehlers-Danlos syndrome (hEDS) remains unknown.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Whole exome sequencing (WES) was undertaken on 174 EDS patients recruited from a national diagnostic service for complex EDS and a specialist clinic for hEDS. Patients had already undergone expert phenotyping, laboratory investigation and gene sequencing, but were without a genetic diagnosis. Filtered WES data were reviewed for genes underlying Mendelian disorders and loci reported in EDS linkage, transcriptome and genome-wide association studies (GWAS). A genetic burden analysis (Minor Allele Frequency (MAF) &lt;0.05) incorporating 248 Avon Longitudinal Study of Parents and Children (ALSPAC) controls sequenced as part of the UK10K study was undertaken using TASER methodology.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Heterozygous pathogenic (P) or likely pathogenic (LP) variants were identified in known EDS and Loeys-Dietz (LDS) genes. Multiple variants of uncertain significance where segregation and functional analysis may enable reclassification were found in genes associated with EDS, LDS, heritable thoracic aortic disease (HTAD), Mendelian disorders with EDS symptomatology and syndromes with EDS-like features. Genetic burden analysis revealed a number of novel loci, although none reached the threshold for genome-wide significance. Variants with biological plausibility were found in genes and pathways not currently associated with EDS or HTAD.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>We demonstrate the clinical utility of large panel-based sequencing and WES for patients with complex EDS in distinguishing rare EDS subtypes, LDS and related syndromes. Although many of the P and LP variants reported in this cohort would be identified with current panel testing, they were not at the time of this study, highlighting the use of extended panels and WES as a clinical tool for complex EDS. Our results are consistent with the complex genetic architecture of EDS and suggest a number of novel hEDS and HTAD candidate genes and pathways.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2023-109329","type":"journal-article","created":{"date-parts":[[2023,10,9]],"date-time":"2023-10-09T08:18:13Z","timestamp":1696839493000},"page":"232-238","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["Genetic complexity of diagnostically unresolved Ehlers-Danlos syndrome"],"prefix":"10.1136","volume":"61","author":[{"given":"Anthony M","family":"Vandersteen","sequence":"first","affiliation":[{"name":"Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada"},{"name":"Faculty of Medicine, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada"},{"name":"Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, 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Glasgow and Clyde, Glasgow, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J","family":"Toddie-Moore","sequence":"additional","affiliation":[{"name":"Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Vandrovcova","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Street Institute of Neurology, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Darlay","sequence":"additional","affiliation":[{"name":"Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1988-5059","authenticated-orcid":false,"given":"Javier","family":"Santoyo-Lopez","sequence":"additional","affiliation":[{"name":"Edinburgh Genomics, University of Edinburgh, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Meynert","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit, University of Edinburgh, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"NIHR BioResource","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanadi","family":"Kazkaz","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University College London Hospitals NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney","family":"Grahame","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University College London Hospitals NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole","family":"Cummings","sequence":"additional","affiliation":[{"name":"Ehlers-Danlos Syndrome National Diagnostic Service, London North West University Healthcare NHS Trust, Northwick Park Hospital, Harrow, UK"},{"name":"Department of Metabolism, Digestion and Reproduction Section of Genetics and Genomics, Imperial College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Bartlett","sequence":"additional","affiliation":[{"name":"Ehlers-Danlos Syndrome National Diagnostic Service, London North West University Healthcare NHS Trust, Northwick Park Hospital, Harrow, UK"},{"name":"Department of Metabolism, Digestion and Reproduction Section of Genetics and Genomics, Imperial College London, London, 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Ehlers-Danlos syndromes: revised Nosology, Villefranche,447 1997. Ehlers-Danlos national foundation (USA) and Ehlers-Danlos support group (UK). 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