{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T16:49:39Z","timestamp":1764262179984,"version":"3.46.0"},"reference-count":35,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004735","name":"the Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2021JJ30390"],"award-info":[{"award-number":["2021JJ30390"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Hunan Provincial Natural Science Foundation of China","award":["2023JJ40343","2024JJ5219"],"award-info":[{"award-number":["2023JJ40343","2024JJ5219"]}]},{"name":"the Special fund of the Hunan provincial key laboratory of pediatric orthopedics","award":["2023TP1019"],"award-info":[{"award-number":["2023TP1019"]}]},{"name":"the Project of Clinical Research Center for Hereditary Birth Defects and Rare Diseases of Hunan Province","award":["2023S-K4053"],"award-info":[{"award-number":["2023S-K4053"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background\/Objectives: Mosaic variegated aneuploidy (MVA) is a rare chromosomal instability disorder. Biallelic variants in SMC5, a core component of the DNA repair machinery, cause Atelis Syndrome, characterized by severe growth failure and multi-system abnormalities. This study aimed to identify the genetic cause in a patient with MVA and a distinct, milder phenotype. Methods: We conducted comprehensive clinical and cytogenetic assessments, chromosomal karyotyping, and trio-based exome sequencing on a proband with hypospadias and chromosomal instability. Identified variants were validated by Sanger sequencing and assessed for pathogenicity using ACMG\/AMP guidelines. Results: Cytogenetic analysis revealed near-tetraploidy (9.7%) and MVA (46.9%). Exome sequencing identified novel compound heterozygous SMC5 variants, a nonsense c.2221G&gt;T (p.Glu741Ter) and a missense c.3065A&gt;G (p.Asn1022Ser), both predicted to disrupt SMC5\/6 complex function. The proband presented with hypospadias and mild developmental delay but lacked the severe neurological, cardiac, or hematological manifestations typical of Atelis Syndrome. Karyotype analysis showed a distinct pattern of chromosomal abnormalities, including a high frequency of marker chromosomes. Conclusions: This report expands the genotypic and phenotypic spectrum of SMC5-related disorders, confirming its association with MVA\/near-tetraploidy and describing a novel attenuated clinical presentation. The findings highlight distinct cytogenetic patterns potentially differentiating DNA repair-defective MVA from other subtypes.<\/jats:p>","DOI":"10.3390\/diagnostics15233022","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T16:31:52Z","timestamp":1764261112000},"page":"3022","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Recessive SMC5 Variants in a Family with Near-Tetraploidy\/Mosaic Variegated Aneuploidy"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8673-1589","authenticated-orcid":false,"given":"Yongjia","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Hunan Children\u2019s Hospital, The Affiliated Children\u2019s Hospital of Xiangya School of Medicine, Central South University, Changsha 410007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Hunan Children\u2019s Hospital, The Affiliated Children\u2019s Hospital of Xiangya School of Medicine, Central South University, Changsha 410007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Hunan Children\u2019s Hospital, School of Pediatrics, University of South China, Changsha 410007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Songting","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pediatric Healthcare, Hunan Children\u2019s Hospital, The Affiliated Children\u2019s Hospital of Xiangya School of Medicine, Central South University, Changsha 410007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Hunan Children\u2019s Hospital, The Affiliated Children\u2019s Hospital of Xiangya School of Medicine, Central South University, Changsha 410007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Hunan Children\u2019s Hospital, The Affiliated Children\u2019s Hospital of Xiangya School of Medicine, Central South University, Changsha 410007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Hunan Children\u2019s Hospital, The Affiliated Children\u2019s Hospital of Xiangya School of Medicine, Central South University, Changsha 410007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Hunan Children\u2019s Hospital, The Affiliated Children\u2019s Hospital of Xiangya School of Medicine, Central South University, Changsha 410007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Hunan Children\u2019s Hospital, The Affiliated Children\u2019s Hospital of Xiangya School of Medicine, Central South University, Changsha 410007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sha","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pediatric Healthcare, Hunan Children\u2019s Hospital, The Affiliated Children\u2019s Hospital of Xiangya School of Medicine, Central South University, Changsha 410007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/ajmg.1580","article-title":"Cancer-prone syndrome of mosaic variegated aneuploidy and total premature chromatid separation: Report of five infants","volume":"104","author":"Kajii","year":"2001","journal-title":"Am. J. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/ajmg.10281","article-title":"High risk of malignancy in mosaic variegated aneuploidy syndrome","volume":"109","author":"Jacquemont","year":"2002","journal-title":"Am. J. Med. Genet."},{"key":"ref_3","first-page":"287","article-title":"Mosaic variegated aneuploidy with microcephaly: A new human mitotic mutant?","volume":"34","author":"Warburton","year":"1991","journal-title":"Ann. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1038\/ng1449","article-title":"Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B","volume":"36","author":"Hanks","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1053\/j.gastro.2013.06.001","article-title":"Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are risk factors for colorectal cancer","volume":"145","author":"Weren","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"eabd5914","DOI":"10.1126\/sciadv.abq5914","article-title":"Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility","volume":"8","author":"Osorio","year":"2022","journal-title":"Sci Adv."},{"key":"ref_7","first-page":"e170079","article-title":"Biallelic MAD2L1BP (p31comet) mutation is associated with mosaic aneuploidy and juvenile granulosa cell tumors","volume":"5","author":"Hellmuth","year":"2023","journal-title":"JCI Insight"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1038\/ng.3883","article-title":"Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation","volume":"49","author":"Yost","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_9","first-page":"e105535","article-title":"Chromosomal instability by mutations in the novel minor spliceosome component CENATAC","volume":"40","author":"Oghabian","year":"2021","journal-title":"EMBO J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1038\/ng.822","article-title":"Mutations in CEP57 cause mosaic variegated aneuploidy syndrome","volume":"43","author":"Snape","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_11","first-page":"100256","article-title":"Mosaic variegated aneuploidy syndrome with tetraploidy and predisposition to male infertility triggered by mutant CEP192","volume":"5","author":"Guo","year":"2024","journal-title":"HGG Adv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6664","DOI":"10.1038\/s41467-022-34349-8","article-title":"Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy","volume":"13","author":"Grange","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/s41576-024-00762-6","article-title":"Mosaic variegated aneuploidy in development, ageing and cancer","volume":"25","author":"Malumbres","year":"2024","journal-title":"Nat. Rev. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/j.cell.2016.01.033","article-title":"Condensin-based chromosome organization from bacteria to vertebrates","volume":"164","author":"Hirano","year":"2016","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nrm.2016.30","article-title":"SMC complexes: From DNA to chromosomes","volume":"17","author":"Uhlmann","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1146\/annurev-genet-112618-043633","article-title":"Organization of chromosomal DNA by SMC complexes","volume":"53","author":"Yatskevich","year":"2019","journal-title":"Annu. Rev. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1038\/ncb1466","article-title":"Smc5-Smc6 mediate DNA double-strand-break repair","volume":"8","author":"Ira","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3377","DOI":"10.1038\/sj.emboj.7601218","article-title":"Human SMC5\/6 complex promotes sister chromatid homologous recombination","volume":"25","author":"Potts","year":"2006","journal-title":"EMBO J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4777","DOI":"10.1073\/pnas.0500537102","article-title":"A SUMO ligase is part of a nuclear multiprotein complex","volume":"102","author":"Zhao","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1016\/j.str.2015.10.004","article-title":"Kite proteins: A superfamily of SMC\/kleisin partners","volume":"23","author":"Palecek","year":"2015","journal-title":"Structure"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1128\/MCB.25.1.185-196.2005","article-title":"Nse2, a component of the Smc5-6 complex, is a SUMO ligase","volume":"25","author":"Andrews","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kolesar, P., Stejskal, K., Potesil, D., Murray, J.M., and Palecek, J.J. (2022). Role of Nse1 subunit as a ubiquitin ligase. Cells, 11.","DOI":"10.3390\/cells11010165"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1146\/annurev-genet-102108-134233","article-title":"Cohesin: Its roles and mechanisms","volume":"43","author":"Nasmyth","year":"2009","journal-title":"Annu. Rev. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1101\/gad.194746.112","article-title":"Condensins: Universal organizers of chromosomes with diverse functions","volume":"26","author":"Hirano","year":"2012","journal-title":"Genes. Dev."},{"key":"ref_25","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_26","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"Durbin R; 1000 Genome Project Data Processing Subgroup. The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ebbert, M.T., Wadsworth, M.E., Staley, L.A., Hoyt, K.L., Pickett, B., Miller, J., Duce, J., Kauwe, J.S.K., and Ridge, P.G. (2016). Evaluating the necessity of PCR duplicate removal from next-generation sequencing data and a comparison of approaches. BMC Bioinform., 17.","DOI":"10.1186\/s12859-016-1097-3"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ng.806","article-title":"A framework for variation discovery and genotyping using next-generation DNA sequencing data","volume":"43","author":"DePristo","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1038\/s41436-019-0552-8","article-title":"SMAD6 is frequently mutated in nonsyndromic radioulnar synostosis","volume":"21","author":"Yang","year":"2019","journal-title":"Genet. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8507","DOI":"10.1074\/jbc.M809139200","article-title":"Architecture of the Smc5\/6 complex of Saccharomyces cerevisiae reveals a unique interaction between the Nse5-6 subcomplex and the hinge regions of Smc5 and Smc6","volume":"284","author":"Duan","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1038\/s41594-023-01015-6","article-title":"The multi-functional Smc5\/6 complex in genome protection and disease","volume":"30","author":"Peng","year":"2023","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1038\/s41594-024-01319-1","article-title":"Cryo-EM structures of Smc5\/6 in multiple states reveal its assembly and functional mechanisms","volume":"31","author":"Li","year":"2024","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1253671","DOI":"10.1126\/science.1253671","article-title":"Proteomics reveals dynamic assembly of repair complexes during bypass of DNA cross-links","volume":"348","author":"Smeenk","year":"2015","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/nrm.2016.58","article-title":"Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers","volume":"17","author":"Schwertman","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/23\/3022\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T16:43:58Z","timestamp":1764261838000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/23\/3022"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,27]]},"references-count":35,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["diagnostics15233022"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics15233022","relation":{},"ISSN":["2075-4418"],"issn-type":[{"type":"electronic","value":"2075-4418"}],"subject":[],"published":{"date-parts":[[2025,11,27]]}}}