{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:53:47Z","timestamp":1791320027453,"version":"4.3.1"},"reference-count":50,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T00:00:00Z","timestamp":1745884800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["T32-MH014677"],"award-info":[{"award-number":["T32-MH014677"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["P30AR074992"],"award-info":[{"award-number":["P30AR074992"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01AR067715"],"award-info":[{"award-number":["R01AR067715"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000097","name":"National Center for Research Resources","doi-asserted-by":"publisher","award":["1S10RR022984-01A1"],"award-info":[{"award-number":["1S10RR022984-01A1"]}],"id":[{"id":"10.13039\/100000097","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["UL1TR002345"],"award-info":[{"award-number":["UL1TR002345"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["P01HD084387"],"award-info":[{"award-number":["P01HD084387"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R03HD104065"],"award-info":[{"award-number":["R03HD104065"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["P50HD103525"],"award-info":[{"award-number":["P50HD103525"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["1S10OD018091-01"],"award-info":[{"award-number":["1S10OD018091-01"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2025,4,17]]},"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Scoliosis is the most common paediatric spinal deformity. More than 80% of scoliosis is idiopathic and appears during the adolescent growth spurt. Spinal fusion surgery is often required for patients with progressive adolescent idiopathic scoliosis (AIS), and the genetic risk factors for severe disease (defined here as curve &gt;35 degrees) are largely unknown.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>To explore the role of rare variants in severe AIS, exome sequence data from 1221 individuals with AIS were compared with both 1397 in-house European ancestry controls and 56885 gnomAD non-Finish European controls. Segregation analysis of variants in prioritised genes was performed in additional family members. A replication study was performed using the Geisinger MyCode cohort. <jats:italic>FNDC1<\/jats:italic> function was investigated in <jats:italic>fndc1<\/jats:italic> null mutant zebrafish.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Rare variants were enriched in 84 genes, including <jats:italic>RAF1<\/jats:italic> (Noonan syndrome), <jats:italic>FBN1<\/jats:italic> (Marfan syndrome) and <jats:italic>FNDC1,<\/jats:italic> in individuals with severe AIS. <jats:italic>FNDC1<\/jats:italic>, which had previously been associated with joint hypermobility, harboured missense variants in 4.0% of individuals with AIS compared with 2.3% of controls (p=0.00764, OR=1.78). <jats:italic>FNDC1<\/jats:italic> variants segregated with AIS in five multiplex families with incomplete penetrance. In addition, <jats:italic>FNDC1<\/jats:italic> rare variants were also associated with scoliosis in the Geisinger MyCode cohort (p=0.0002, OR=3.6). Disruption of the <jats:italic>fndc1<\/jats:italic> locus in zebrafish resulted in increased bone mineral density.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>We broadened the phenotype associated with <jats:italic>RAF1<\/jats:italic> and <jats:italic>FBN1<\/jats:italic> variants and identified <jats:italic>FNDC1<\/jats:italic> as a novel gene associated with severe AIS. Mechanistic alterations of bone mineral density or joint hypermobility may explain the association of <jats:italic>FNDC1<\/jats:italic> missense variants with AIS.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2024-110586","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T01:40:11Z","timestamp":1745977211000},"page":"427-435","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Rare missense variants in <i>FNDC1<\/i> are associated with severe adolescent idiopathic scoliosis"],"prefix":"10.1136","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0661-4081","authenticated-orcid":false,"given":"Wu-Lin","family":"Charng","sequence":"first","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine in St Louis, St Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabe","family":"Haller","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Washington University School of Medicine in St Louis, St Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Whittle","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine in St Louis, St Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Momchil","family":"Nikolov","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine in St Louis, St Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Addison","family":"Avery","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine in St Louis, St Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Morcuende","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, University of Iowa, Iowa City, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Giampietro","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Illinois Chicago, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Raggio","sequence":"additional","affiliation":[{"name":"Hospital for Special Surgery, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne E","family":"Justice","sequence":"additional","affiliation":[{"name":"Department of Population Health Sciences, Geisinger Health, Danville, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha T","family":"Strande","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Geisinger Health, Danville, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Seeley","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Geisinger Health, Danville, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale L","family":"Bodian","sequence":"additional","affiliation":[{"name":"Geisinger, North Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6790-2194","authenticated-orcid":false,"given":"Carol A","family":"Wise","sequence":"additional","affiliation":[{"name":"Scottish Rite Hospital and University of Texas Southwestern, Dallas, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane S","family":"Sepich","sequence":"additional","affiliation":[{"name":"Developmental Biology, Washington University School of Medicine in St Louis, St Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew B","family":"Dobbs","sequence":"additional","affiliation":[{"name":"Paley Orthopedic & Spine Institute, West Palm Beach, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina A","family":"Gurnett","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Pediatrics, Washington University School of Medicine in St Louis, St Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"2025101712401853000_62.7.427.1","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1302\/0301-620X.50B1.24","article-title":"Familial (idiopathic) scoliosis. A family survey","volume":"50","author":"Wynne-Davies","year":"1968","journal-title":"J Bone Joint Surg Br"},{"key":"2025101712401853000_62.7.427.2","doi-asserted-by":"crossref","DOI":"10.1155\/2014\/370134","article-title":"Generalised joint hypermobility in caucasian girls with idiopathic scoliosis: relation with age, curve size, and curve pattern","volume":"2014","author":"Czaprowski","year":"2014","journal-title":"ScientificWorldJournal"},{"key":"2025101712401853000_62.7.427.3","doi-asserted-by":"publisher","DOI":"10.1007\/s11832-012-0457-4"},{"key":"2025101712401853000_62.7.427.4","doi-asserted-by":"crossref","unstructured":"P\u00e9rez-Machado G , Berenguer-Pascual E , Bovea-Marco M , et al . From genetics to epigenetics to unravel the etiology of adolescent idiopathic scoliosis. Bone 2020;140. doi:10.1016\/j.bone.2020.115563","DOI":"10.1016\/j.bone.2020.115563"},{"key":"2025101712401853000_62.7.427.5","doi-asserted-by":"crossref","DOI":"10.1186\/1748-7161-6-22","article-title":"Joint hypermobility in children with idiopathic scoliosis: SOSORT award 2011 winner","volume":"6","author":"Czaprowski","year":"2011","journal-title":"Scoliosis"},{"key":"2025101712401853000_62.7.427.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0030-5898(05)70091-2"},{"key":"2025101712401853000_62.7.427.7","doi-asserted-by":"publisher","DOI":"10.1038\/ng.974"},{"key":"2025101712401853000_62.7.427.8","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2639"},{"key":"2025101712401853000_62.7.427.9","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms7452","article-title":"A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females","volume":"6","author":"Sharma","year":"2015","journal-title":"Nat Commun"},{"key":"2025101712401853000_62.7.427.10","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-018-06705-0","article-title":"A missense variant in SLC39A8 is associated with severe idiopathic scoliosis","volume":"9","author":"Haller","year":"2018","journal-title":"Nat Commun"},{"key":"2025101712401853000_62.7.427.11","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-019-11596-w","article-title":"Genome-wide association study identifies 14 previously unreported susceptibility loci for adolescent idiopathic scoliosis in Japanese","volume":"10","author":"Kou","year":"2019","journal-title":"Nat Commun"},{"key":"2025101712401853000_62.7.427.12","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0072802","article-title":"Identification of a susceptibility locus for severe adolescent idiopathic scoliosis on chromosome 17q24.3","volume":"8","author":"Miyake","year":"2013","journal-title":"PLoS One"},{"key":"2025101712401853000_62.7.427.13","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx291"},{"key":"2025101712401853000_62.7.427.14","doi-asserted-by":"publisher","DOI":"10.1172\/JCI77262"},{"key":"2025101712401853000_62.7.427.15","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1534\/g3.114.015669","article-title":"Exome sequencing identifies a rare HSPG2 variant associated with familial idiopathic scoliosis","volume":"5","author":"Baschal","year":"2014","journal-title":"G3 (Bethesda)"},{"key":"2025101712401853000_62.7.427.16","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2018-105877"},{"key":"2025101712401853000_62.7.427.17","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu224"},{"key":"2025101712401853000_62.7.427.18","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv463"},{"key":"2025101712401853000_62.7.427.19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/0471250953.bi1110s43","article-title":"From FastQ Data to High\u2010Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline","volume":"43","author":"Van der Auwera","year":"2013","journal-title":"CP in Bioinformatics"},{"key":"2025101712401853000_62.7.427.20","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"2025101712401853000_62.7.427.21","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2892"},{"key":"2025101712401853000_62.7.427.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"2025101712401853000_62.7.427.23","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq559"},{"key":"2025101712401853000_62.7.427.24","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"2025101712401853000_62.7.427.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2013.08.280"},{"key":"2025101712401853000_62.7.427.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.08.016"},{"key":"2025101712401853000_62.7.427.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.03.012"},{"key":"2025101712401853000_62.7.427.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.spinee.2015.05.013"},{"key":"2025101712401853000_62.7.427.29","doi-asserted-by":"publisher","DOI":"10.2106\/00004623-200110000-00006"},{"key":"2025101712401853000_62.7.427.30","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2021-108186"},{"key":"2025101712401853000_62.7.427.31","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2015.0168"},{"key":"2025101712401853000_62.7.427.32","doi-asserted-by":"publisher","DOI":"10.1093\/dnares\/8.2.85"},{"key":"2025101712401853000_62.7.427.33","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms12792","article-title":"Genome-wide association study for acute otitis media in children identifies FNDC1 as disease contributing gene","volume":"7","author":"van Ingen","year":"2016","journal-title":"Nat Commun"},{"key":"2025101712401853000_62.7.427.34","first-page":"6680","article-title":"Rutin suppresses FNDC1 expression in bone marrow mesenchymal stem cells to inhibit postmenopausal osteoporosis","volume":"11","author":"Xiao","year":"2019","journal-title":"Am J Transl Res"},{"key":"2025101712401853000_62.7.427.35","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3570"},{"key":"2025101712401853000_62.7.427.36","doi-asserted-by":"publisher","DOI":"10.1002\/art.20376"},{"key":"2025101712401853000_62.7.427.37","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2015.30"},{"key":"2025101712401853000_62.7.427.38","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0161347","article-title":"Transcriptome-Wide Expression Profiling in Skin Fibroblasts of Patients with Joint Hypermobility Syndrome\/Ehlers-Danlos Syndrome Hypermobility Type","volume":"11","author":"Chiarelli","year":"2016","journal-title":"PLoS One"},{"key":"2025101712401853000_62.7.427.39","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2020.595653","article-title":"The Genetic Architecture of High Bone Mass","volume":"11","author":"Gregson","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2025101712401853000_62.7.427.40","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2011.42"},{"key":"2025101712401853000_62.7.427.41","doi-asserted-by":"publisher","DOI":"10.1007\/s00586-012-2465-y"},{"key":"2025101712401853000_62.7.427.42","doi-asserted-by":"publisher","DOI":"10.1097\/01.BRS.0000084265.15201.D5"},{"key":"2025101712401853000_62.7.427.43","doi-asserted-by":"crossref","DOI":"10.1038\/s41413-020-0089-0","article-title":"The cartilage matrisome in adolescent idiopathic scoliosis","volume":"8","author":"Wise","year":"2020","journal-title":"Bone Res"},{"key":"2025101712401853000_62.7.427.44","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-019-0698-x"},{"key":"2025101712401853000_62.7.427.45","doi-asserted-by":"publisher","DOI":"10.1097\/BRS.0000000000002809"},{"key":"2025101712401853000_62.7.427.46","doi-asserted-by":"publisher","DOI":"10.1038\/ng2078"},{"key":"2025101712401853000_62.7.427.47","doi-asserted-by":"crossref","unstructured":"Wang X , Yue M , Cheung JPY , et al . Impaired glycine neurotransmission causes adolescent idiopathic scoliosis. J Clin Invest 2024;134. doi:10.1172\/JCI168783","DOI":"10.1172\/JCI168783"},{"key":"2025101712401853000_62.7.427.48","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/3.12.2175"},{"key":"2025101712401853000_62.7.427.49","doi-asserted-by":"publisher","DOI":"10.1038\/ng1293-351"},{"key":"2025101712401853000_62.7.427.50","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-019-0575-7"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2024-110586","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T19:40:25Z","timestamp":1760730025000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2024-110586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,29]]},"references-count":50,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,6,24]]},"published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1136\/jmg-2024-110586"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2024-110586","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,29]]}}}