{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:03:45Z","timestamp":1792789425672,"version":"4.5.0"},"reference-count":52,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T00:00:00Z","timestamp":1628121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hong Kong Health and Medical Research Fund","award":["06171406"],"award-info":[{"award-number":["06171406"]}]},{"name":"Tam Sai Kit Endowment Fund","award":["Not applied"],"award-info":[{"award-number":["Not applied"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Congenital scoliosis (CS) is a lateral curvature of the spine resulting from congenital vertebral malformations (CVMs) and affects 0.5\u20131\/1000 live births. The copy number variant (CNV) at chromosome 16p11.2 has been implicated in CVMs and recent studies identified a compound heterozygosity of 16p11.2 microdeletion and TBX6 variant\/haplotype causing CS in multiple cohorts, which explains about 5\u201310% of the affected cases. Here, we studied the genetic etiology of CS by analyzing CNVs in a cohort of 67 patients with congenital hemivertebrae and 125 family controls. We employed both candidate gene and family-based approaches to filter CNVs called from whole exome sequencing data. This identified 12 CNVs in four scoliosis-associated genes (TBX6, NOTCH2, DSCAM, and SNTG1) as well as eight recessive and 64 novel rare CNVs in 15 additional genes. Some candidates, such as DHX40, NBPF20, RASA2, and MYSM1, have been found to be associated with syndromes with scoliosis or implicated in bone\/spine development. In particular, the MYSM1 mutant mouse showed spinal deformities. Our findings suggest that, in addition to the 16p11.2 microdeletion, other CNVs are potentially important in predisposing to CS.<\/jats:p>","DOI":"10.3390\/genes12081213","type":"journal-article","created":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T21:43:53Z","timestamp":1628199833000},"page":"1213","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Identification of Copy Number Variants in a Southern Chinese Cohort of Patients with Congenital Scoliosis"],"prefix":"10.3390","volume":"12","author":[{"given":"Wenjing","family":"Lai","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Feng","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4052-818X","authenticated-orcid":false,"given":"Ming","family":"Yue","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3213-7373","authenticated-orcid":false,"given":"Prudence W. H.","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa N. T.","family":"Choi","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9407-2256","authenticated-orcid":false,"given":"You-Qiang","family":"Song","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith D. K.","family":"Luk","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7052-0875","authenticated-orcid":false,"given":"Jason Pui Yin","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8684-5199","authenticated-orcid":false,"given":"Bo","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.6064\/2012\/152365","article-title":"Genetic Aspects of Congenital and Idiopathic Scoliosis","volume":"2012","author":"Giampietro","year":"2012","journal-title":"Scientifica"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.2106\/00004623-195537060-00012","article-title":"The incidence of scoliosis in the state of Delaware; a study of 50,000 minifilms of the chest made during a survey for tuberculosis","volume":"37","author":"Shands","year":"1955","journal-title":"J. Bone Jt. Surg. Am. Vol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1136\/jmg.12.3.280","article-title":"Congenital vertebral anomalies: Aetiology and relationship to spina bifida cystica","volume":"12","year":"1975","journal-title":"J. Med. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.2106\/00004623-198264080-00003","article-title":"The natural history of congenital scoliosis. A study of two hundred and fifty-one patients","volume":"64","author":"McMaster","year":"1982","journal-title":"J. Bone Jt. Surg. Am. Vol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.2106\/00004623-199910000-00002","article-title":"Natural History of Congenital Kyphosis and Kyphoscoliosis. A Study of One Hundred and Twelve Patients","volume":"81","author":"McMaster","year":"1999","journal-title":"J. Bone Jt. Surg. Am. Vol."},{"key":"ref_6","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. Primers"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.cell.2011.05.011","article-title":"Vertebrate Segmentation: From Cyclic Gene Networks to Scoliosis","volume":"145","year":"2011","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.1242\/dev.069310","article-title":"Somitogenesis","volume":"139","author":"Maroto","year":"2012","journal-title":"Development"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1159\/000345329","article-title":"Clinical, Genetic and Environmental Factors Associated with Congenital Vertebral Malformations","volume":"4","author":"Giampietro","year":"2012","journal-title":"Mol. Syndr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1126\/science.1098918","article-title":"Large-Scale Copy Number Polymorphism in the Human Genome","volume":"305","author":"Sebat","year":"2004","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3216","DOI":"10.1007\/s11999-014-3766-8","article-title":"Are copy number variants associated with adolescent idiopathic scoliosis?","volume":"472","author":"Buchan","year":"2014","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1136\/jmedgenet-2018-105877","article-title":"Distal chromosome 16p11.2 duplications containing SH2B1 in patients with scoliosis","volume":"56","author":"Sadler","year":"2019","journal-title":"J. Med. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1002\/ajmg.a.36401","article-title":"Scoliosis and vertebral anomalies: Additional abnormal phenotypes associated with chromosome 16p11.2 rearrangement","volume":"164","author":"Khanna","year":"2014","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1056\/NEJMoa1406829","article-title":"TBX6 Null Variants and a Common Hypomorphic Allele in Congenital Scoliosis","volume":"372","author":"Wu","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1002\/humu.23168","article-title":"Compound Heterozygosity for Null Mutations and a Common Hypomorphic Risk Haplotype in TBX6 Causes Congenital Scoliosis","volume":"38","author":"Takeda","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1111\/cge.12918","article-title":"Autosomal recessive variations of TBX6, from congenital scoliosis to spondylocostal dysostosis","volume":"91","author":"Lefebvre","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1002\/jor.24805","article-title":"Genetic variants of TBX6 and TBXT identified in patients with congenital scoliosis in Southern China","volume":"39","author":"Feng","year":"2020","journal-title":"J. Orthop. Res."},{"key":"ref_18","first-page":"313","article-title":"Advances in congenital vertebral malformation caused by genomic copy number variation","volume":"54","author":"Liu","year":"2016","journal-title":"Zhonghua Wai Ke Za Zhi"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.jspd.2014.04.014","article-title":"Genomic Analyses of Patients with Unexplained Early-Onset Scoliosis","volume":"2","author":"Gao","year":"2014","journal-title":"Spine Deform."},{"key":"ref_20","first-page":"1","article-title":"Mutations in COMP cause familial carpal tunnel syndrome","volume":"11","author":"Li","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"i884","DOI":"10.1093\/bioinformatics\/bty560","article-title":"Fastp: An ultra-fast all-in-one FASTQ preprocessor","volume":"34","author":"Chen","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1093\/bioinformatics\/bts526","article-title":"A robust model for read count data in exome sequencing experiments and implications for copy number variant calling","volume":"28","author":"Plagnol","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_25","first-page":"388","article-title":"Congenital scoliosis: An up-to-date","volume":"8","author":"Burnei","year":"2015","journal-title":"J. Med. Life"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/ejhg.2017.42","article-title":"Validation of copy number variation analysis for next-generation sequencing diagnostics","volume":"25","author":"Ellingford","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1093\/hmg\/ddq571","article-title":"Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes","volume":"20","author":"Sharma","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s00439-004-1121-y","article-title":"SNTG1, the gene encoding gamma1-syntrophin: A candidate gene for idiopathic scoliosis","volume":"115","author":"Bashiardes","year":"2004","journal-title":"Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"116022","DOI":"10.1016\/j.bone.2021.116022","article-title":"Scoliosis with cognitive impairment in a girl with 8q11.21q11.23 microdeletion and SNTG1 disruption","volume":"150","author":"Tassano","year":"2021","journal-title":"Bone"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.ajhg.2019.06.001","article-title":"Paralog Studies Augment Gene Discovery: DDX and DHX Genes","volume":"105","author":"Paine","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.1038\/ng2084","article-title":"Genomic rearrangements and sporadic disease","volume":"39","author":"Lupski","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.cell.2012.02.054","article-title":"A Mechanism for Gene-Environment Interaction in the Etiology of Congenital Scoliosis","volume":"149","author":"Sparrow","year":"2012","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1086\/505332","article-title":"NOTCH2 Mutations Cause Alagille Syndrome, a Heterogeneous Disorder of the Notch Signaling Pathway","volume":"79","author":"McDaniell","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/ejhg.2011.125","article-title":"Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu\u2013Cheney syndrome","volume":"20","author":"Gray","year":"2011","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_35","unstructured":"Adam, M.P., and Ardinger, H.H. (1993). 1q21.1 Recurrent Microdeletion. Gene Reviews(R), University of Washington."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1159\/000450971","article-title":"Interstitial 1q21.1 Microdeletion Is Associated with Severe Skeletal Anomalies, Dysmorphic Face and Moderate Intellectual Disability","volume":"7","author":"Gamba","year":"2016","journal-title":"Mol. Syndr."},{"key":"ref_37","first-page":"100089","article-title":"Detection of de novo genetic variants in Mayer-Rokitansky-Kuster-Hauser syndrome by whole genome sequencing","volume":"4","author":"Pan","year":"2019","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol. X"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1097\/00007611-200093020-00022","article-title":"Scoliosis associated with typical Mayer-Rokitansky-K\u00fcster-Hauser syndrome","volume":"93","author":"Fisher","year":"2000","journal-title":"South. Med. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"11473","DOI":"10.1073\/pnas.1324128111","article-title":"Next-generation sequencing identifies rare variants associated with Noonan syndrome","volume":"111","author":"Chen","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.2106\/00004623-200110000-00006","article-title":"Spinal deformities in Noonan syndrome: A clinical review of sixty cases","volume":"83","author":"Lee","year":"2001","journal-title":"J. Bone Jt. Surg. Am. Vol."},{"key":"ref_41","first-page":"1","article-title":"Deubiquitinase MYSM1 Is Essential for Normal Bone Formation and Mesenchymal Stem Cell Differentiation","volume":"6","author":"Li","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.immuni.2011.11.010","article-title":"Control of B Cell Development by the Histone H2A Deubiquitinase MYSM1","volume":"35","author":"Jiang","year":"2011","journal-title":"Immunity"},{"key":"ref_43","first-page":"1","article-title":"Novel skin phenotypes revealed by a genome-wide mouse reverse genetic screen","volume":"5","author":"Vancollie","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"DiTommaso, T., Jones, L.K., Cottle, D.L., Gerdin, A.-K., Vancollie, V.E., Watt, F.M., Ramirez-Solis, R., Bradley, A., Steel, K.P., and Sundberg, J.P. (2014). Identification of Genes Important for Cutaneous Function Revealed by a Large Scale Reverse Genetic Screen in the Mouse. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004705"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"125","DOI":"10.3121\/cmr.1.2.125","article-title":"Congenital and Idiopathic Scoliosis: Clinical and Genetic Aspects","volume":"1","author":"Giampietro","year":"2003","journal-title":"Clin. Med. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"242","DOI":"10.2174\/1566523219666190924120307","article-title":"A Recurrent Rare SOX9 Variant (M469V) is Associated with Congenital Vertebral Malformations","volume":"19","author":"Wu","year":"2019","journal-title":"Curr. Gene Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/s10038-019-0698-x","article-title":"Identification of novel FBN1 variations implicated in congenital scoliosis","volume":"65","author":"Lin","year":"2019","journal-title":"J. Hum. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1002\/ajmg.a.61607","article-title":"KIAA1217: A novel candidate gene associated with isolated and syndromic vertebral malformations","volume":"182","author":"Wu","year":"2020","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1086\/301618","article-title":"Mistakes happen: Somatic mutation and disease","volume":"61","author":"Qian","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S1097-2765(00)80135-5","article-title":"Somatic Mutation in Individual Liver Cysts Supports a Two-Hit Model of Cystogenesis in Autosomal Dominant Polycystic Kidney Disease","volume":"2","author":"Watnick","year":"1998","journal-title":"Mol. Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/12511","article-title":"The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: A new facet to Knudson\u2019s \u2018two-hit\u2019 hypothesis","volume":"5","author":"Lamlum","year":"1999","journal-title":"Nat. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s12031-019-01277-0","article-title":"NF1 Somatic Mutation in Dystrophic Scoliosis","volume":"68","author":"Margraf","year":"2019","journal-title":"J. Mol. Neurosci."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/8\/1213\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:41:12Z","timestamp":1760164872000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/8\/1213"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,5]]},"references-count":52,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["genes12081213"],"URL":"https:\/\/doi.org\/10.3390\/genes12081213","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,5]]}}}