{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T11:26:28Z","timestamp":1762082788548,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T00:00:00Z","timestamp":1671753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011912","name":"Taipei Veterans General Hospital","doi-asserted-by":"publisher","award":["V105E20-001-MY2","MOST 111-2628-B-038-025","MOST 110-2314-B-038-161","MOST 110-2321-B-038-002","111-5812-001-400"],"award-info":[{"award-number":["V105E20-001-MY2","MOST 111-2628-B-038-025","MOST 110-2314-B-038-161","MOST 110-2321-B-038-002","111-5812-001-400"]}],"id":[{"id":"10.13039\/501100011912","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["V105E20-001-MY2","MOST 111-2628-B-038-025","MOST 110-2314-B-038-161","MOST 110-2321-B-038-002","111-5812-001-400"],"award-info":[{"award-number":["V105E20-001-MY2","MOST 111-2628-B-038-025","MOST 110-2314-B-038-161","MOST 110-2321-B-038-002","111-5812-001-400"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Taipei Medical University","award":["V105E20-001-MY2","MOST 111-2628-B-038-025","MOST 110-2314-B-038-161","MOST 110-2321-B-038-002","111-5812-001-400"],"award-info":[{"award-number":["V105E20-001-MY2","MOST 111-2628-B-038-025","MOST 110-2314-B-038-161","MOST 110-2321-B-038-002","111-5812-001-400"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Adolescent idiopathic scoliosis (AIS) is a three-dimensional spinal curvature deformity that appears in the adolescent period. In this study, we performed whole-exome sequencing on 11 unrelated Taiwanese patients with a Cobb\u2019s angle greater than 40 degrees. Our results identified more than 200 potential pathogenic rare variants, however, most of which were carried only by one individual. By in silico pathogenicity annotation studies, we found that TTN, CLCN1, and SOX8 were the most important genes, as multiple pathogenic variants were within these genes. Furthermore, biological functional annotation indicated critical roles of these AIS candidate genes in the skeletal muscle. Importantly, a pathogenic variant on SOX8 was shared by over 35% of the patients. These results highlighted TTN, CLCN1, and SOX8 as the most likely susceptibility genes for severe AIS.<\/jats:p>","DOI":"10.3390\/jpm13010032","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T04:40:39Z","timestamp":1672116039000},"page":"32","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Whole-Exome Sequencing Identifies Genetic Variants for Severe Adolescent Idiopathic Scoliosis in a Taiwanese Population"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0247-1984","authenticated-orcid":false,"given":"Min-Rou","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Po-Hsin","family":"Chou","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Traumatology, Taipei Veterans General Hospital, Taipei 112, Taiwan"},{"name":"School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuei-Jung","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7918-8218","authenticated-orcid":false,"given":"Jafit","family":"Ting","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia-Ying","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7693-5959","authenticated-orcid":false,"given":"Wan-Hsuan","family":"Chou","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1735-8255","authenticated-orcid":false,"given":"Gan-Hong","family":"Lin","sequence":"additional","affiliation":[{"name":"Master Program in Clinical Genomics and Proteomics, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0375-1427","authenticated-orcid":false,"given":"Jan-Gowth","family":"Chang","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine, China Medical University Hospital, Taichung 404, Taiwan"},{"name":"School of Medicine, China Medical University, Taichung 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiro","family":"Ikegawa","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Science (IMS, RIKEN), Tokyo 108-8639, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0942-8332","authenticated-orcid":false,"given":"Shih-Tien","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Traumatology, Taipei Veterans General Hospital, Taipei 112, Taiwan"},{"name":"School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"},{"name":"Kinmen Hospital, Ministry of Health and Welfare, Kinmen 891, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Chiao","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Master Program in Clinical Genomics and Proteomics, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Integrative Research Center in Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11832-012-0457-4","article-title":"Epidemiology of adolescent idiopathic scoliosis","volume":"7","author":"Konieczny","year":"2013","journal-title":"J. Child Orthop."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"702","DOI":"10.2106\/00004623-198163050-00003","article-title":"Idiopathic scoliosis: Long-term follow-up and prognosis in untreated patients","volume":"63","author":"Weinstein","year":"1981","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15030","DOI":"10.1038\/nrdp.2015.30","article-title":"Adolescent idiopathic scoliosis","volume":"1","author":"Cheng","year":"2015","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1007\/s00586-019-06075-1","article-title":"Treatment of bracing for adolescent idiopathic scoliosis patients: A meta-analysis","volume":"28","author":"Zhang","year":"2019","journal-title":"Eur. Spine J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13013-016-0095-6","article-title":"Bracing for Adolescent Idiopathic Scoliosis (AIS) and Scheuermann Kyphosis: The issue of overtreatment in Greece","volume":"11","author":"Karavidas","year":"2016","journal-title":"Scoliosis Spinal Disord."},{"key":"ref_6","first-page":"111","article-title":"Adolescent idiopathic scoliosis: Review and current concepts","volume":"64","author":"Reamy","year":"2001","journal-title":"Am. Fam. Physician"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13013-016-0105-8","article-title":"Genetics and pathogenesis of idiopathic scoliosis","volume":"11","author":"Grauers","year":"2016","journal-title":"Scoliosis Spinal Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1038\/ng.974","article-title":"A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis","volume":"43","author":"Takahashi","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/ng.2639","article-title":"Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis","volume":"45","author":"Kou","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.ajhg.2015.06.012","article-title":"A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis","volume":"97","author":"Ogura","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5271","DOI":"10.1093\/hmg\/ddu224","article-title":"Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis","volume":"23","author":"Buchan","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1093\/hmg\/ddv463","article-title":"A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis","volume":"25","author":"Haller","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s12967-019-1805-7","article-title":"Adiponectin regulates bone mass in AIS osteopenia via RANKL\/OPG and IL6 pathway","volume":"17","author":"Zhang","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1007\/s00586-010-1385-y","article-title":"Polymorphism in vitamin D receptor is associated with bone mineral density in patients with adolescent idiopathic scoliosis","volume":"19","author":"Suh","year":"2010","journal-title":"Eur. Spine J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.bone.2018.11.017","article-title":"Alterations of the gut microbiome and plasma proteome in Chinese patients with adolescent idiopathic scoliosis","volume":"120","author":"Shen","year":"2019","journal-title":"Bone"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1748-7161-1-9","article-title":"Association between adolescent idiopathic scoliosis prevalence and age at menarche in different geographic latitudes","volume":"1","author":"Grivas","year":"2006","journal-title":"Scoliosis"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1111\/j.1600-079X.2009.00669.x","article-title":"Serum melatonin levels in adolescent idiopathic scoliosis prediction and prevention for curve progression\u2013A prospective study","volume":"46","author":"Machida","year":"2009","journal-title":"J. Pineal Res."},{"key":"ref_18","first-page":"1","article-title":"Estrogen promotes the onset and development of idiopathic scoliosis via disproportionate endochondral ossification of the anterior and posterior column in a bipedal rat model","volume":"50","author":"Zheng","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1001\/jama.282.15.1427","article-title":"A population-based study of school scoliosis screening","volume":"282","author":"Yawn","year":"1999","journal-title":"JAMA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41525-021-00178-9","article-title":"Genetic profiles of 103,106 individuals in the Taiwan Biobank provide insights into the health and history of Han Chinese","volume":"6","author":"Wei","year":"2021","journal-title":"NPJ Genom. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"Auton","year":"2015","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"D840","DOI":"10.1093\/nar\/gkw971","article-title":"The ExAC browser: Displaying reference data information from over 60 000 exomes","volume":"45","author":"Karczewski","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"W199","DOI":"10.1093\/nar\/gkz401","article-title":"WebGestalt 2019: Gene set analysis toolkit with revamped UIs and APIs","volume":"47","author":"Liao","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3439","DOI":"10.1093\/bioinformatics\/bti525","article-title":"BioMart and Bioconductor: A powerful link between biological databases and microarray data analysis","volume":"21","author":"Durinck","year":"2005","journal-title":"Bioinformatics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"R7","DOI":"10.1186\/gb-2004-6-1-r7","article-title":"The Mammalian Phenotype Ontology as a tool for annotating, analyzing and comparing phenotypic information","volume":"6","author":"Smith","year":"2005","journal-title":"Genome Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_29","unstructured":"(2021). The Gene Ontology resource: Enriching a GOld mine. Nucleic Acids Res., 49, D325\u2013D334."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s12041-019-1115-0","article-title":"Myotonia congenita: Mutation spectrum of CLCN1 in Spanish patients","volume":"98","author":"Milla","year":"2019","journal-title":"J. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"293","DOI":"10.3233\/JND-160158","article-title":"Increasing Role of Titin Mutations in Neuromuscular Disorders","volume":"3","author":"Savarese","year":"2016","journal-title":"J. Neuromuscular Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1002\/humu.22611","article-title":"A rising titan: TTN review and mutation update","volume":"35","author":"Chauveau","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s00401-020-02257-0","article-title":"Making sense of missense variants in TTN-related congenital myopathies","volume":"141","author":"Rees","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1002\/humu.10063","article-title":"Myotonia caused by mutations in the muscle chloride channel gene CLCN1","volume":"19","author":"Pusch","year":"2002","journal-title":"Hum. Mutat."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1002\/(SICI)1097-4598(199704)20:4<411::AID-MUS2>3.0.CO;2-D","article-title":"Familial mixed congenital myopathy with rigid spine phenotype","volume":"20","author":"Reichmann","year":"1997","journal-title":"Muscle Nerve"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Sk\u00e1lov\u00e1, D., Z\u00eddkov\u00e1, J., Voh\u00e1\u0148ka, S., Mazanec, R., Mu\u0161ov\u00e1, Z., Vondr\u00e1\u010dek, P., Mr\u00e1zov\u00e1, L., Kraus, J., R\u00e9blov\u00e1, K., and Fajkusov\u00e1, L. (2013). CLCN1 mutations in Czech patients with myotonia congenita, in silico analysis of novel and known mutations in the human dimeric skeletal muscle chloride channel. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082549"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"dmm048901","DOI":"10.1242\/dmm.048901","article-title":"Saturation mutagenesis defines novel mouse models of severe spine deformity","volume":"14","author":"Rios","year":"2021","journal-title":"Dis. Model. Mech."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.ydbio.2005.03.010","article-title":"Impact of transcription factor Sox8 on oligodendrocyte specification in the mouse embryonic spinal cord","volume":"281","author":"Stolt","year":"2005","journal-title":"Dev. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"104870","DOI":"10.1016\/j.nbd.2020.104870","article-title":"Glial cells involvement in spinal muscular atrophy: Could SMA be a neuroinflammatory disease?","volume":"140","author":"Abati","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1093\/brain\/aws339","article-title":"Oligodendrocyte dysfunction in the pathogenesis of amyotrophic lateral sclerosis","volume":"136","author":"Philips","year":"2013","journal-title":"Brain"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Aranmolate, A., Tse, N., and Colognato, H. (2017). Myelination is delayed during postnatal brain development in the mdx mouse model of Duchenne muscular dystrophy. BMC Neurosci., 18.","DOI":"10.1186\/s12868-017-0381-0"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1006\/geno.1999.6060","article-title":"The SOX8 gene is located within 700 kb of the tip of chromosome 16p and is deleted in a patient with ATR-16 syndrome","volume":"63","author":"Pfeifer","year":"2000","journal-title":"Genomics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"29769","DOI":"10.1074\/jbc.M301539200","article-title":"Sox8 is a specific marker for muscle satellite cells and inhibits myogenesis","volume":"278","author":"Schmidt","year":"2003","journal-title":"J. Biol. Chem."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/13\/1\/32\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:49:22Z","timestamp":1760147362000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/13\/1\/32"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,23]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["jpm13010032"],"URL":"https:\/\/doi.org\/10.3390\/jpm13010032","relation":{},"ISSN":["2075-4426"],"issn-type":[{"type":"electronic","value":"2075-4426"}],"subject":[],"published":{"date-parts":[[2022,12,23]]}}}