{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T14:46:57Z","timestamp":1787582817014,"version":"build-2736575974"},"reference-count":76,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,9]],"date-time":"2025-02-09T00:00:00Z","timestamp":1739059200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science Committee of the Ministry of Science and Higher Education of the Republic of Kazakhstan","award":["AP19579029"],"award-info":[{"award-number":["AP19579029"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Congenital spinal deformities (CSDs) are rare but severe conditions caused by abnormalities in vertebral development during embryogenesis. These deformities, including scoliosis, kyphosis, and lordosis, significantly impair patients\u2019 quality of life and present challenges in diagnosis and treatment. This review integrates genetic, molecular, and developmental insights to provide a comprehensive framework for classifying and understanding CSDs. Traditional classification systems based on morphological criteria, such as failures in vertebral formation, segmentation, or mixed defects, are evaluated alongside newer molecular-genetic approaches. Advances in genetic technologies, including whole-exome sequencing, have identified critical genes and pathways involved in somitogenesis and sclerotome differentiation, such as TBX6, DLL3, and PAX1, as well as key signaling pathways like Wnt, Notch, Hedgehog, BMP, and TGF-\u03b2. These pathways regulate vertebral development, and their disruption leads to skeletal abnormalities. The review highlights the potential of molecular classifications based on genetic mutations and developmental stage-specific defects to enhance diagnostic precision and therapeutic strategies. Early diagnosis using non-invasive prenatal testing (NIPT) and emerging tools like CRISPR-Cas9 gene editing offer promising but ethically complex avenues for intervention. Limitations in current classifications and the need for further research into epigenetic and environmental factors are discussed. This study underscores the importance of integrating molecular genetics into clinical practice to improve outcomes for patients with CSDs.<\/jats:p>","DOI":"10.3390\/jcm14041113","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T03:39:47Z","timestamp":1739158787000},"page":"1113","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Reviewing the Genetic and Molecular Foundations of Congenital Spinal Deformities: Implications for Classification and Diagnosis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6558-6546","authenticated-orcid":false,"given":"Diana","family":"Samarkhanova","sequence":"first","affiliation":[{"name":"National Center for Biotechnology, Astana 010000, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3414-0610","authenticated-orcid":false,"given":"Maxat","family":"Zhabagin","sequence":"additional","affiliation":[{"name":"National Center for Biotechnology, Astana 010000, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8852-7934","authenticated-orcid":false,"given":"Nurbek","family":"Nadirov","sequence":"additional","affiliation":[{"name":"National Center for Biotechnology, Astana 010000, Kazakhstan"},{"name":"Department of Orthopedics, Mother and Child Health Center, University Medical Center, Astana 010000, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Li, M., Nie, Q., Liu, J., and Jiang, Z. (2024). Prevalence of scoliosis in children and adolescents: A systematic review and meta-analysis. Front. Pediatr., 12.","DOI":"10.3389\/fped.2024.1399049"},{"key":"ref_2","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. Syndromol."},{"key":"ref_3","unstructured":"(2024, November 15). Korean Statistical Information Service. Available online: https:\/\/kosis.kr\/eng\/."},{"key":"ref_4","first-page":"1","article-title":"Incidence rate of congenital scoliosis estimated from a nationwide health insurance database","volume":"11","author":"Kwon","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S0030-5898(05)70094-8","article-title":"Congenital spine deformities","volume":"30","author":"Lonstein","year":"1999","journal-title":"Orthop. Clin. North Am."},{"key":"ref_6","unstructured":"Winter, R.B., Leonard, A.S., and Smith, D.E. (1983). Congenital Deformities of the Spine, Thieme-Stratton Inc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1007\/s00586-011-1972-6","article-title":"Surgical treatment of severe congenital scoliosis with unilateral unsegmented bar by concave costovertebral joint release and both-ends wedge osteotomy via posterior approach","volume":"21","author":"Li","year":"2011","journal-title":"Eur. Spine J."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jung, C., Asbach, P., and Niehues, S.M. (2021). Are congenital cervical block vertebrae a risk factor for adjacent segment disease? A retrospective cross-sectional CT and MR imaging study. Diagnostics, 12.","DOI":"10.3390\/diagnostics12010090"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1097\/BRS.0b013e3181ac0045","article-title":"Classification of congenital scoliosis and Kyphosis","volume":"34","author":"Kawakami","year":"2009","journal-title":"Spine"},{"key":"ref_10","first-page":"1","article-title":"Coupling Failure as the Forth Category in the Classification of Congenital Spinal Deformity","volume":"1","author":"Kawakami","year":"2018","journal-title":"Sci. Repos."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.spinee.2004.10.044","article-title":"Embryology of the spine and associated congenital abnormalities","volume":"5","author":"Kaplan","year":"2005","journal-title":"Spine J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1038\/s12276-020-0482-1","article-title":"Understanding paraxial mesoderm development and SCLEROTOME specification for Skeletal Repair","volume":"52","author":"Tani","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3437","DOI":"10.1242\/dev.125.17.3437","article-title":"Dermomyotomal origin of the ribs as revealed by extirpation and transplantation experiments in chick and quail embryos","volume":"125","author":"Kato","year":"1998","journal-title":"Development"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/0092-8674(94)90009-4","article-title":"Patterning of mammalian somites by surface ectoderm and notochord: Evidence for sclerotome induction by a hedgehog homolog","volume":"79","author":"Fan","year":"1994","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1016\/0092-8674(94)90008-6","article-title":"Ectopic expression of sonic hedgehog alters dorsal-ventral patterning of somites","volume":"79","author":"Johnson","year":"1994","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1006\/dbio.1999.9261","article-title":"Notochord-dependent expression of MFH1 and PAX1 cooperates to maintain the proliferation of sclerotome cells during the vertebral column development","volume":"210","author":"Furumoto","year":"1999","journal-title":"Dev. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wu, W., Kong, X., Jia, Y., Jia, Y., Ou, W., Dai, C., Li, G., and Gao, R. (2022). An overview of PAX1: Expression, function and regulation in development and diseases. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.1051102"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/tera.1420520604","article-title":"Functional involvement of Pax-1 in somite development: Somite dysmorphogenesis in chick embryos treated with Pax-1 paired-box antisense oligodeoxynucleotide","volume":"52","author":"Smith","year":"1995","journal-title":"Teratology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.gendis.2014.07.005","article-title":"Bone morphogenetic protein (BMP) signaling in development and human diseases","volume":"1","author":"Wang","year":"2014","journal-title":"Genes Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1126\/science.1974085","article-title":"Murine developmental control genes","volume":"249","author":"Kessel","year":"1990","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ydbio.2010.04.024","article-title":"Hox genes and regional patterning of the Vertebrate Body Plan","volume":"344","author":"Mallo","year":"2010","journal-title":"Dev. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.jbi.2005.06.001","article-title":"A bioinformatics framework for genotype\u2013phenotype correlation in humans with Marfan syndrome caused by FBN1 gene mutations","volume":"39","author":"Baumgartner","year":"2006","journal-title":"J. Biomed. Inform."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1136\/jmedgenet-2014-102964","article-title":"A novel syndrome of Klippel-Feil Anomaly, myopathy, and characteristic facies is linked to a null mutation in MYO18B","volume":"52","author":"Alazami","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1002\/ajmg.a.33471","article-title":"Autosomal dominant spondylocostal dysostosis in three generations of a Macedonian family: Negative mutation analysis of DLL3, MESP2, HES7, and LFNG","volume":"152A","author":"Gucev","year":"2010","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/1750-1172-6-56","article-title":"VACTERL\/Vater Association","volume":"6","author":"Solomon","year":"2011","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/ejhg.2011.181","article-title":"Alagille syndrome: Pathogenesis, diagnosis and management","volume":"20","author":"Turnpenny","year":"2011","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Uehara, M., Takahashi, J., and Kosho, T. (2023). Spinal deformity in Ehlers\u2013Danlos Syndrome: Focus on musculocontractural type. Genes, 14.","DOI":"10.3390\/genes14061173"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13023-024-03040-0","article-title":"Molecular landscape of congenital vertebral malformations: Recent discoveries and Future Directions","volume":"19","author":"Szoszkiewicz","year":"2024","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_29","first-page":"287","article-title":"Exome sequencing reveals de novo variants in congenital scoliosis","volume":"11","author":"Murakami","year":"2021","journal-title":"J. Pediatr. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Meijer, W.H.M., and Sonnen, K.F. (2024). From signalling oscillations to somite formation. Curr. Opin. Syst. Biol., 39.","DOI":"10.1016\/j.coisb.2024.100520"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1002\/wdev.34","article-title":"Scoliosis and segmentation defects of the vertebrae","volume":"1","author":"Eckalbar","year":"2012","journal-title":"WIREs Dev. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0925-4773(02)00394-5","article-title":"The mouse rib-vertebrae mutation is a hypomorphic TBX6 allele","volume":"119","author":"Schlautmann","year":"2002","journal-title":"Mech. Dev."},{"key":"ref_33","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_34","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_35","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1136\/jmg.40.5.333","article-title":"Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis","volume":"40","author":"Turnpenny","year":"2003","journal-title":"J. Med. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1159\/000527043","article-title":"Identification of a novel nonsense variant in the DLL3 gene underlying spondylocostal dysostosis in a consanguineous Pakistani family","volume":"14","author":"Khan","year":"2023","journal-title":"Mol. Syndromol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1387\/ijdb.072332sr","article-title":"A comparative analysis of Meox1 and Meox2 in the developing somites and limbs of the chick embryo","volume":"51","author":"Reijntjes","year":"2007","journal-title":"Int. J. Dev. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.ajhg.2012.11.016","article-title":"Mutations in MEOX1, encoding mesenchyme homeobox 1, Cause Klippel-Feil Anomaly","volume":"92","author":"Mohamed","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Mallo, M. (2016). The Axial Musculoskeletal System. Kaufman\u2019s Atlas of Mouse Development Supplement, Academic Press.","DOI":"10.1016\/B978-0-12-800043-4.00013-0"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5399","DOI":"10.1242\/dev.126.23.5399","article-title":"PAX1 and PAX9 synergistically regulate vertebral column development","volume":"126","author":"Peters","year":"1999","journal-title":"Development"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1242\/dev.00240","article-title":"PAX1 and PAX9 activate Bapx1 to induce chondrogenic differentiation in the sclerotome","volume":"130","author":"Rodrigo","year":"2003","journal-title":"Development"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.ydbio.2009.06.006","article-title":"Lack of the mesodermal homeodomain protein MEOX1 disrupts sclerotome polarity and leads to a remodeling of the cranio-cervical joints of the axial skeleton","volume":"332","author":"Skuntz","year":"2009","journal-title":"Dev. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/s41413-024-00342-8","article-title":"Wnt\/\u03b2-catenin signaling components and mechanisms in bone formation, homeostasis, and disease","volume":"12","author":"Hu","year":"2024","journal-title":"Bone Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/nrn1847","article-title":"Notch signalling in Vertebrate Neural Development","volume":"7","author":"Louvi","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Ohba, S. (2020). Hedgehog signaling in skeletal development: Roles of Indian hedgehog and the mode of its action. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186665"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41422-023-00918-9","article-title":"The roles and regulatory mechanisms of TGF-\u03b2 and BMP signaling in bone and cartilage development, homeostasis and disease","volume":"34","author":"Wu","year":"2024","journal-title":"Cell Res."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Li, Z., Zhao, S., Cai, S., Zhang, Y., Wang, L., Niu, Y., Li, X., Hu, J., Chen, J., and Wang, S. (2020). The mutational burden and oligogenic inheritance in Klippel-Feil Syndrome. BMC Musculoskelet. Disord., 21.","DOI":"10.1186\/s12891-020-03229-x"},{"key":"ref_48","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_49","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s00439-019-01993-y","article-title":"Targeted panel sequencing establishes the implication of planar cell polarity pathway and involves new candidate genes in neural tube defect disorders","volume":"138","author":"Beaumont","year":"2019","journal-title":"Hum. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e364","DOI":"10.1038\/oncsis.2017.69","article-title":"Non-canonical wnt\/PCP signalling in cancer: FZD6 takes Centre Stage","volume":"6","author":"Corda","year":"2017","journal-title":"Oncogenesis"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/nature09129","article-title":"Planar cell polarity breaks bilateral symmetry by controlling ciliary positioning","volume":"466","author":"Song","year":"2010","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1056\/NEJMoa060651","article-title":"Mutations in VANGL1 associated with neural-tube defects","volume":"356","author":"Kibar","year":"2007","journal-title":"N Engl. J. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2795","DOI":"10.1002\/ajmg.a.37263","article-title":"Rare variants in the notch signaling pathway describe a novel type of autosomal recessive klippel\u2013feil syndrome","volume":"167","author":"Karaca","year":"2015","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_54","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":"2017","journal-title":"Clin. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/ng0797-243","article-title":"Alagille syndrome is caused by mutations in human JAGGED1, which encodes a ligand for notch1","volume":"16","author":"Li","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1242\/dev.000836","article-title":"The negative regulation of Mesp2 by Mouse Ripply2 is required to establish the Rostro-caudal patterning within a somite","volume":"134","author":"Morimoto","year":"2007","journal-title":"Development"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e33068","DOI":"10.7554\/eLife.33068","article-title":"Ripply2 recruits proteasome complex for TBX6 degradation to define segment border during murine somitogenesis","volume":"7","author":"Zhao","year":"2018","journal-title":"eLife"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Turnpenny, P.D. (2015). Classification and etiologic dissection of vertebral segmentation anomalies. Mol. Genet. Pediatr. Orthop. Disord., 105\u2013130.","DOI":"10.1007\/978-1-4939-2169-0_7"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6382","DOI":"10.1073\/pnas.0608449104","article-title":"Indian hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone","volume":"104","author":"Maeda","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1111\/j.1399-0004.2005.00520.x","article-title":"An analysis of PAX1 in the development of vertebral malformations","volume":"68","author":"Giampietro","year":"2005","journal-title":"Clin. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12964-018-0220-7","article-title":"A highlight on sonic hedgehog pathway","volume":"16","author":"Carballo","year":"2018","journal-title":"Cell Commun. Signal."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1126\/science.280.5368.1455","article-title":"Noggin, cartilage morphogenesis, and joint formation in the Mammalian Skeleton","volume":"280","author":"Brunet","year":"1998","journal-title":"Science"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.ydbio.2004.04.015","article-title":"A new role for BMP5 during limb development acting through the synergic activation of SMAD and MAPK PATHWAYS","volume":"272","author":"Montero","year":"2004","journal-title":"Dev. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Bandyopadhyay, A., Tsuji, K., Cox, K., Harfe, B.D., Rosen, V., and Tabin, C.J. (2006). Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet., 2.","DOI":"10.1371\/journal.pgen.0020216"},{"key":"ref_65","first-page":"5704","article-title":"TAK1 regulates SOX9 expression in chondrocytes and is essential for postnatal development of the growth plate and articular cartilages","volume":"126","author":"Gao","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1093\/hmg\/ddad117","article-title":"COL11A2 as a candidate gene for vertebral malformations and congenital scoliosis","volume":"32","author":"Rebello","year":"2023","journal-title":"Hum. Mol. Genet."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1093\/hmg\/ddp496","article-title":"Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies","volume":"19","author":"Ye","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.joca.2019.05.005","article-title":"TGF-\u03b2 signaling in intervertebral disc health and disease","volume":"27","author":"Chen","year":"2019","journal-title":"Osteoarthr. Cartil."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ydbio.2007.07.040","article-title":"Deletion of TGFBR2 in Prx1-Cre expressing mesenchyme results in defects in development of the long bones and joints","volume":"310","author":"Seo","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Wang, W., Song, B., Anbarchian, T., Shirazyan, A., Sadik, J.E., and Lyons, K.M. (2016). Smad2 and Smad3 regulate chondrocyte proliferation and differentiation in the growth plate. PLOS Genet., 12.","DOI":"10.1371\/journal.pgen.1006352"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/ejhg.2012.250","article-title":"Non-invasive prenatal testing for single gene disorders: Exploring the ethics","volume":"21","author":"Deans","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1056\/NEJMoa2031054","article-title":"CRISPR-Cas9 gene editing for sickle cell disease and \u03b2-thalassemia","volume":"384","author":"Frangoul","year":"2021","journal-title":"N Engl. J. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e2004832117","DOI":"10.1073\/pnas.2004832117","article-title":"Frequent loss of heterozygosity in CRISPR-Cas9\u2013edited early human embryos","volume":"118","author":"Zohren","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1097\/00007632-198207000-00002","article-title":"Cervical spine anomalies in fetal alcohol syndrome","volume":"7","author":"Tredwell","year":"1982","journal-title":"Spine"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1177\/000992288402300611","article-title":"Valproic acid and congenital malformations","volume":"23","author":"Bantz","year":"1984","journal-title":"Clin. Pediatr."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1002\/(SICI)1096-8628(20000214)90:4<303::AID-AJMG8>3.0.CO;2-Q","article-title":"Oculoauriculovertebral abnormalities in children of diabetic mothers","volume":"90","author":"Yankowitz","year":"2000","journal-title":"Am. J. Med. Genet."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/4\/1113\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:29:57Z","timestamp":1760027397000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/4\/1113"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,9]]},"references-count":76,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["jcm14041113"],"URL":"https:\/\/doi.org\/10.3390\/jcm14041113","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,9]]}}}