{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:06:19Z","timestamp":1788948379662,"version":"build-2803163510"},"reference-count":20,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100014535","name":"Center for Individualized Medicine, Mayo Clinic","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014535","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The cohesin complex, composed of SMC1, SMC3, RAD21, and STAG1\/STAG2, is essential for chromosome cohesion, DNA repair, and transcriptional regulation. Pathogenic variants in cohesin components cause cohesinopathies. The classical characteristics of cohesinopathies include developmental delay (DD), intellectual disability (ID), feeding difficulties, hypotonia, short stature, hearing loss, and dysmorphic features. Here, we present a 5\u2010year\u2010old boy with classical cohesinopathy features, including DD\/ID and feeding difficulties, along with non\u2010classical features such as hypoglycemia, recurrent fever, and immunodeficiency. Trio exome sequencing identified a novel\n                    <jats:italic>de novo<\/jats:italic>\n                    missense variant of uncertain significance (NM_005862.3:c.643G&gt;A(p.Val215Ile)) in the\n                    <jats:italic>STAG1<\/jats:italic>\n                    gene. The variant localizes to the RAD21 interaction interface, and molecular dynamics (MD) simulations revealed conformational changes comparable to other\n                    <jats:italic>STAG1<\/jats:italic>\n                    variants reported as likely pathogenic in patients, supporting a deleterious effect which may disrupt the STAG1\u2010RAD21 interaction interface. This case expands the phenotypic and molecular spectrum of STAG1\u2010related cohesinopathy and advances our understanding of the disease mechanism.\n                  <\/jats:p>","DOI":"10.1111\/cge.70246","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T09:07:06Z","timestamp":1788944826000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel\n                    <i>De Novo STAG1<\/i>\n                    Variant at the\n                    <scp>RAD21<\/scp>\n                    Binding Interface Is Associated With Hypoglycemia, Recurrent Fever, Immunodeficiency and Features of Classical Cohesinopathies"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5269-8971","authenticated-orcid":false,"given":"Hafiz Muhammad Jafar","family":"Hussain","sequence":"first","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Quantitative Health Sciences Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7073-0525","authenticated-orcid":false,"given":"Michael","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Computational Structural Genomics Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin  Milwaukee Wisconsin USA"},{"name":"Data Science Institute, Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5503-7324","authenticated-orcid":false,"given":"Stephanie L.","family":"Safgren","sequence":"additional","affiliation":[{"name":"Division of Oncology Research Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7691-8334","authenticated-orcid":false,"given":"Joseph D.","family":"Farris","sequence":"additional","affiliation":[{"name":"Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2521-2937","authenticated-orcid":false,"given":"Deepak","family":"Panwar","sequence":"additional","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Quantitative Health Sciences Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7162-4005","authenticated-orcid":false,"given":"Sarah Allen","family":"Thurman","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1009-6555","authenticated-orcid":false,"given":"Karthik","family":"Muthusamy","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1640-6780","authenticated-orcid":false,"given":"Raul","family":"Urrutia","sequence":"additional","affiliation":[{"name":"Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myra J.","family":"Wick","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6030-1903","authenticated-orcid":false,"given":"Filippo Pinto","family":"e Vairo","sequence":"additional","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Medicine, Division of Gastroenterology and Hepatology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2946-5795","authenticated-orcid":false,"given":"Eric W.","family":"Klee","sequence":"additional","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Quantitative Health Sciences Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Clinical Genomics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"issue":"7","key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1136\/jmedgenet-2016-104468","article-title":"STAG1 Mutations Cause a Novel Cohesinopathy Characterised by Unspecific Syndromic Intellectual Disability","volume":"54","author":"Lehalle D.","year":"2017","journal-title":"Journal of Medical Genetics"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.3389\/fgene.2012.00171","article-title":"Diverse Developmental Disorders From the One Ring: Distinct Molecular Pathways Underlie the Cohesinopathies","volume":"3","author":"Horsfield J. A.","year":"2012","journal-title":"Frontiers in Genetics"},{"issue":"3","key":"e_1_2_10_4_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1003382","article-title":"Genome\u2010Wide Control of RNA Polymerase II Activity by Cohesin","volume":"9","author":"Schaaf C. A.","year":"2013","journal-title":"PLoS Genetics"},{"issue":"5","key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1002\/wdev.190","article-title":"Etiology and Pathogenesis of the Cohesinopathies","volume":"4","author":"Zakari M.","year":"2015","journal-title":"Wiley Interdisciplinary Reviews: Developmental Biology"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.2147\/TACG.S34457","article-title":"Genetic Basis of Cohesinopathies","volume":"6","author":"Barbero J. L.","year":"2013","journal-title":"Application of Clinical Genetics"},{"issue":"12","key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1016\/j.yexcr.2012.03.016","article-title":"Cohesin in Determining Chromosome Architecture","volume":"318","author":"Haering C. H.","year":"2012","journal-title":"Experimental Cell Research"},{"issue":"6","key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1534\/g3.116.029462","article-title":"Genetic Interactions Between the Meiosis\u2010Specific Cohesin Components, STAG3, REC8, and RAD21L","volume":"6","author":"Ward A.","year":"2016","journal-title":"G3: Genes, Genomes, Genetics"},{"issue":"3","key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/s41436-018-0085-6","article-title":"Clinical Exome Sequencing Reveals Locus Heterogeneity and Phenotypic Variability of Cohesinopathies","volume":"21","author":"Yuan B.","year":"2019","journal-title":"Genetics in Medicine"},{"issue":"2","key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1111\/cga.12454","article-title":"Cohesinopathy Presenting With Microtia, Facial Palsy, and Hearing Loss Caused by STAG1 Pathogenic Variant","volume":"62","author":"Funato M.","year":"2022","journal-title":"Congenit Anom (Kyoto)"},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","DOI":"10.1177\/2050313X241277123","article-title":"A Novel STAG1 Variant Associated With Congenital Clubfoot and Microphthalmia: A Case Report","volume":"12","author":"Bregvadze K.","year":"2024","journal-title":"SAGE Open Medical Case Reports"},{"issue":"9","key":"e_1_2_10_12_1","doi-asserted-by":"crossref","DOI":"10.3390\/genes15091184","article-title":"A Novel De Novo STAG1 Variant in Monozygotic Twins With Neurodevelopmental Disorder: New Insights in Clinical Heterogeneity","volume":"15","author":"Cipriano L.","year":"2024","journal-title":"Genes (Basel)"},{"issue":"8","key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.3390\/genes12081116","article-title":"Novel STAG1 Frameshift Mutation in a Patient Affected by a Syndromic Form of Neurodevelopmental Disorder","volume":"12","author":"Di Muro E.","year":"2021","journal-title":"Genes"},{"issue":"1","key":"e_1_2_10_14_1","doi-asserted-by":"crossref","DOI":"10.1002\/mgg3.2342","article-title":"Mutation Profiling in South African Patients With Cornelia de Lange Syndrome Phenotype","volume":"12","author":"Seymour H.","year":"2024","journal-title":"Molecular Genetics & Genomic Medicine"},{"key":"e_1_2_10_15_1","doi-asserted-by":"crossref","DOI":"10.3389\/fped.2025.1648430","article-title":"A Novel Frameshift STAG1 Variant Exhibiting Haploinsufficiency due to the Nonsense\u2010Mediated mRNA Decay: A Case Report and Literature Review","volume":"13","author":"Jiang C.","year":"2025","journal-title":"Frontiers in Pediatrics"},{"issue":"3","key":"e_1_2_10_16_1","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/ahg.70023","article-title":"A Novel Variant of STAG1 Gene and Literature Review","volume":"90","author":"Xie M.","year":"2026","journal-title":"Annals of Human Genetics"},{"issue":"1","key":"e_1_2_10_17_1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1186\/s13059-023-02982-1","article-title":"RAD21 Is the Core Subunit of the Cohesin Complex Involved in Directing Genome Organization","volume":"24","author":"Sun Y.","year":"2023","journal-title":"Genome Biology"},{"key":"e_1_2_10_18_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2022.840002","article-title":"Cohesin\u2010Mediated Chromatin Interactions and Autoimmunity","volume":"13","author":"Chandrasekaran V.","year":"2022","journal-title":"Frontiers in Immunology"},{"issue":"2","key":"e_1_2_10_19_1","doi-asserted-by":"crossref","first-page":"211","DOI":"10.4274\/jcrpe.galenos.2022.2022-4-14","article-title":"Endocrine Evaluation and Homeostatic Model Assessment in Patients With Cornelia de Lange Syndrome","volume":"16","author":"Ascaso \u00c1.","year":"2024","journal-title":"Journal of Clinical Research in Pediatric Endocrinology"},{"issue":"4","key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.bbrc.2005.05.054","article-title":"A Kir2.1 Gain\u2010Of\u2010Function Mutation Underlies Familial Atrial Fibrillation","volume":"332","author":"Xia M.","year":"2005","journal-title":"Biochemical and Biophysical Research Communications"},{"issue":"13","key":"e_1_2_10_21_1","doi-asserted-by":"crossref","first-page":"3523","DOI":"10.1093\/hmg\/ddu064","article-title":"The Familial Alzheimer's Disease APPV717I Mutation Alters APP Processing and Tau Expression in iPSC\u2010Derived Neurons","volume":"23","author":"Muratore C. R.","year":"2014","journal-title":"Human Molecular Genetics"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70246","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.70246","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70246","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T09:07:09Z","timestamp":1788944829000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.70246"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":20,"alternative-id":["10.1111\/cge.70246"],"URL":"https:\/\/doi.org\/10.1111\/cge.70246","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]},"assertion":[{"value":"2026-05-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cge.70246"}}