{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T02:14:36Z","timestamp":1769480076085,"version":"3.49.0"},"reference-count":42,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UC Davis School of Veterinary Medicine Center for Companion Animal Health and Maxine Adler Endowed Chair Funds"},{"name":"Comparative Medical Scientist Training Award","award":["NIH T32 OD 011147"],"award-info":[{"award-number":["NIH T32 OD 011147"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Spondylocostal dysostosis (SCDO) is a rare disorder characterized by congenital malformations of the spine and ribs. SCDO affects 1 in 40,000 human births, with rare cases also reported in dogs. Mutations in DLL3, encoding a critical Notch signaling pathway ligand, account for a majority of human SCDO cases. The remaining cases have variants in HES7, LFNG, MESP2, RIPPLY2, TBX6, and DLL1, which code for proteins in the Notch pathway. A mixed-breed litter of three dogs presented with varying degrees of spinal malformations and underwent comprehensive phenotyping including radiographic and neurologic examination. Two littermates demonstrated classic SCDO features including shortened torsos, vertebral malformations, and rib abnormalities, while a third showed only caudal vertebral truncation. Methods: Short-read whole-genome sequencing was performed on all three animals, followed by variant filtering and analysis using the two severely affected dogs as cases and 173 control dogs of various breeds. Variants were prioritized based on segregation patterns, population frequency, and predicted functional impact using established bioinformatics tools. Results: Variant analysis identified a novel splice acceptor variant in DLL3 (c.650-2A&gt;C). This mutation, located at the splice acceptor site preceding exon 5, is predicted to disrupt critical EGF-like domains and O-fucosylation sites essential for DLL3 protein function. Conclusions: This study identifies a DLL3 splice variant causing SCDO in dogs, demonstrating phenotypic conservation with humans. These findings refine our understanding of genotype\u2013phenotype correlations and demonstrate the value of comparative genomics for rare developmental disorders.<\/jats:p>","DOI":"10.3390\/genes17020131","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T15:48:30Z","timestamp":1769442510000},"page":"131","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Splice Acceptor Variant in DLL3 Is Associated with Spondylocostal Dysostosis in a Litter of Mixed-Breed Dogs"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9028-1114","authenticated-orcid":false,"given":"Scarlett","family":"Varney","sequence":"first","affiliation":[{"name":"Department of Population Health and Reproduction, School of Veterinary Medicine, University of California\u2014Davis, Davis, CA 95616, USA"},{"name":"Graduate Group of Integrative Pathobiology, School of Veterinary Medicine, University of California\u2014Davis, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8062-0028","authenticated-orcid":false,"given":"Karen","family":"Vernau","sequence":"additional","affiliation":[{"name":"Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California\u2014Davis, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7956-0175","authenticated-orcid":false,"given":"Craig","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California\u2014Davis, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3216-3344","authenticated-orcid":false,"given":"Christine","family":"Toedebusch","sequence":"additional","affiliation":[{"name":"Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California\u2014Davis, Davis, CA 95616, USA"},{"name":"Department of Molecular Biosciences, School of Veterinary Medicine, University of California\u2014Davis, Davis, CA 95616, USA"},{"name":"Veterinary Neurology Biorepository, School of Veterinary Medicine, University of California\u2014Davis, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6951-9524","authenticated-orcid":false,"given":"Julia","family":"Vo","sequence":"additional","affiliation":[{"name":"Department of Population Health and Reproduction, School of Veterinary Medicine, University of California\u2014Davis, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7614-7207","authenticated-orcid":false,"given":"Danika","family":"Bannasch","sequence":"additional","affiliation":[{"name":"Department of Population Health and Reproduction, School of Veterinary Medicine, University of California\u2014Davis, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1097\/BRS.0b013e3181ab64e9","article-title":"Spine deformities in rare congenital syndromes: Clinical issues","volume":"34","author":"Campbell","year":"2009","journal-title":"Spine"},{"key":"ref_2","first-page":"159","article-title":"Anomalous Animals","volume":"61","year":"1965","journal-title":"S. Afr. J. Sci."},{"key":"ref_3","unstructured":"Hutt, F.B. (1964). Animal Genetics, The Ronald Press Company."},{"key":"ref_4","first-page":"155","article-title":"A Pathological Study on Deformation of the Vertebral Column in the \u201cShort-Spine Dog\u201d","volume":"9","author":"Ueshima","year":"1961","journal-title":"Jpn. J. Vet. Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Willet, C.E., Makara, M., Reppas, G., Tsoukalas, G., Malik, R., Haase, B., and Wade, C.M. (2015). Canine disorder mirrors human disease: Exonic deletion in HES7 causes autosomal recessive spondylocostal dysostosis in miniature Schnauzer dogs. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117055"},{"key":"ref_6","unstructured":"Adam, M.P., Bick, S., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (2009). Spondylocostal Dysostosis, Autosomal Recessive. GeneReviews, University of Washington."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Umair, M., Younus, M., Shafiq, S., Nayab, A., and Alfadhel, M. (2022). Clinical genetics of spondylocostal dysostosis: A mini review. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.996364"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Nobrega, A., Maia-Fernandes, A.C., and Andrade, R.P. (2021). Altered Cogs of the Clock: Insights into the Embryonic Etiology of Spondylocostal Dysostosis. J. Dev. Biol., 9.","DOI":"10.3390\/jdb9010005"},{"key":"ref_9","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_10","doi-asserted-by":"crossref","unstructured":"Barhoumi, T., Nashabat, M., Alghanem, B., Alhallaj, A., Boudjelal, M., Umair, M., Alarifi, S., Alfares, A., Mohrij, S.A.A., and Alfadhel, M. (2019). Delta Like-1 Gene Mutation: A Novel Cause of Congenital Vertebral Malformation. Front. Genet., 10.","DOI":"10.3389\/fgene.2019.00534"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/74307","article-title":"Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis","volume":"24","author":"Bulman","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1093\/hmg\/ddu534","article-title":"Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects","volume":"24","author":"Sparrow","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1002\/ajmg.a.61549","article-title":"Congenital posterior cervical spine malformation due to biallelic c.240-4T>G RIPPLY2 variant: A discrete entity","volume":"182","author":"Scala","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1086\/498879","article-title":"Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype","volume":"78","author":"Sparrow","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3761","DOI":"10.1093\/hmg\/ddn272","article-title":"Mutation of Hairy-and-Enhancer-of-Split-7 in humans causes spondylocostal dysostosis","volume":"17","author":"Sparrow","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1093\/hmg\/ddt012","article-title":"Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6","volume":"22","author":"Sparrow","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1086\/421053","article-title":"Mutated MESP2 causes spondylocostal dysostosis in humans","volume":"74","author":"Whittock","year":"2004","journal-title":"Am. J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-319-43151-2_1","article-title":"Disordered vertebral and rib morphology in pudgy mice. Structural relationships to human scoliosis","volume":"221","author":"Shapiro","year":"2016","journal-title":"Adv. Anat. Embryol. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/961","article-title":"The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries","volume":"19","author":"Kusumi","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1748-5827.1968.tb04597.x","article-title":"Historical evidence of an unusual deformity in dogs (\u201cshort-spine dog\u201d)","volume":"9","author":"Hansen","year":"1968","journal-title":"J. Small Anim. Pract."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1007\/s00335-025-10123-1","article-title":"The RSPO2 gene is associated with bilateral anterior amelia in Chihuahuas","volume":"36","author":"Chevallier","year":"2025","journal-title":"Mamm. Genome"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: A tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1186\/s13059-023-03023-7","article-title":"Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture","volume":"24","author":"Meadows","year":"2023","journal-title":"Genome Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"D939","DOI":"10.1093\/nar\/gkae928","article-title":"Dog10K: An integrated Dog10K database summarizing canine multi-omics","volume":"53","author":"Zhou","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: Predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"eadg7492","DOI":"10.1126\/science.adg7492","article-title":"Accurate proteome-wide missense variant effect prediction with AlphaMissense","volume":"381","author":"Cheng","year":"2023","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1101\/gr.097857.109","article-title":"Detection of nonneutral substitution rates on mammalian phylogenies","volume":"20","author":"Pollard","year":"2010","journal-title":"Genome Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"D1082","DOI":"10.1093\/nar\/gkad987","article-title":"The UCSC Genome Browser database: 2024 update","volume":"52","author":"Raney","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1089\/cmb.1997.4.311","article-title":"Improved splice site detection in Genie","volume":"4","author":"Reese","year":"1997","journal-title":"J. Comput. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1093\/hmg\/ddq529","article-title":"Notch inhibition by the ligand DELTA-LIKE 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis","volume":"20","author":"Chapman","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1083\/jcb.200503113","article-title":"The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands","volume":"170","author":"Ladi","year":"2005","journal-title":"J. Cell Biol."},{"key":"ref_33","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_34","doi-asserted-by":"crossref","unstructured":"Serth, K., Schuster-Gossler, K., Kremmer, E., Hansen, B., Marohn-Kohn, B., and Gossler, A. (2015). O-fucosylation of DLL3 is required for its function during somitogenesis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0123776"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/nrg2164","article-title":"Splicing in disease: Disruption of the splicing code and the decoding machinery","volume":"8","author":"Wang","year":"2007","journal-title":"Nat. Rev. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"iyae031","DOI":"10.1093\/genetics\/iyae031","article-title":"Mouse Genome Informatics: An integrated knowledgebase system for the laboratory mouse","volume":"227","author":"Baldarelli","year":"2024","journal-title":"Genetics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"D924","DOI":"10.1093\/nar\/gkaa914","article-title":"The mouse Gene Expression Database (GXD): 2021 update","volume":"49","author":"Baldarelli","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome","volume":"347","author":"Uhlen","year":"2015","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/s41422-025-01084-w","article-title":"Structural insights into spliceosome fidelity: DHX35-GPATCH1- mediated rejection of aberrant splicing substrates","volume":"35","author":"Li","year":"2025","journal-title":"Cell Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1007\/s003350010253","article-title":"Canine homolog of the T-box transcription factor T; failure of the protein to bind to its DNA target leads to a short-tail phenotype","volume":"12","author":"Haworth","year":"2001","journal-title":"Mamm. Genome"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Mansour, T.A., Lucot, K., Konopelski, S.E., Dickinson, P.J., Sturges, B.K., Vernau, K.L., Choi, S., Stern, J.A., Thomasy, S.M., and Doring, S. (2018). Whole genome variant association across 100 dogs identifies a frame shift mutation in DISHEVELLED 2 which contributes to Robinow-like syndrome in Bulldogs and related screw tail dog breeds. PLoS Genet., 14.","DOI":"10.1371\/journal.pgen.1007850"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1101\/gad.930601","article-title":"Dynamic expression and essential functions of Hes7 in somite segmentation","volume":"15","author":"Bessho","year":"2001","journal-title":"Genes. Dev."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/2\/131\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T15:59:08Z","timestamp":1769443148000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/2\/131"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,26]]},"references-count":42,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["genes17020131"],"URL":"https:\/\/doi.org\/10.3390\/genes17020131","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,26]]}}}