{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:40:22Z","timestamp":1760402422217,"version":"build-2065373602"},"reference-count":82,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Germline mutations in the X-linked cohesin subunit gene SMC1A have been increasingly recognized as a cause of developmental and epileptic encephalopathy (DEE); however, the underlying basis of its marked phenotypic heterogeneity remains elusive. In our narrative review, starting from all literature-reported clinical cases of SMC1A-related DEE, we propose an integrative framework summarizing all the clinical and genetic features, stratified by mutation type, mosaic fraction, and X-chromosome inactivation (XCI) patterns to provide valuable support for genetic diagnosis and variants, found to date. Also, we discuss how somatic mosaicism and epigenetic variability underlie the clinical diversity of SMC1A-associated epilepsy and systematically describe the entire phenotypic spectrum, from early-onset, therapy-resistant seizures to milder intellectual disability profiles. We further examine how SMC1A mutations perturb cohesin\u2019s canonical roles in chromatin loop formation and sister-chromatid cohesion, leading to widespread transcriptional dysregulation of neurodevelopmental gene networks. Evidence that XCI skewing can ameliorate or exacerbate neuronal cohesin deficits and, thus modulate seizure threshold, is presented.<\/jats:p>","DOI":"10.3390\/genes16101196","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:13:27Z","timestamp":1760361207000},"page":"1196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Linking Genotype to Clinical Features in SMC1A-Related Phenotypes: From Cornelia de Lange Syndrome to Developmental and Epileptic Encephalopathy, a Comprehensive Review"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7882-2432","authenticated-orcid":false,"given":"Maria Francesca","family":"Astorino","sequence":"first","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morpho-Functional Imaging\u2014BIOMORF, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5108-1052","authenticated-orcid":false,"given":"Desir\u00e8e","family":"Speranza","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7697-2347","authenticated-orcid":false,"given":"Giovanni","family":"Luppino","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of Adulthood and Childhood, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Angela","family":"La Rosa","sequence":"additional","affiliation":[{"name":"UOSD of Genetics and Pharmacogenetics, \u201cGaetano Martino\u201d University Hospital, Via Consolare Valeria, 98125 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5213-441X","authenticated-orcid":false,"given":"Silvana","family":"Briuglia","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morpho-Functional Imaging\u2014BIOMORF, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"},{"name":"UOSD of Genetics and Pharmacogenetics, \u201cGaetano Martino\u201d University Hospital, Via Consolare Valeria, 98125 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2082-9855","authenticated-orcid":false,"given":"Marco","family":"Calabr\u00f2","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morpho-Functional Imaging\u2014BIOMORF, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"},{"name":"UOSD of Genetics and Pharmacogenetics, \u201cGaetano Martino\u201d University Hospital, Via Consolare Valeria, 98125 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"973","DOI":"10.4161\/epi.28903","article-title":"Overall and allele-specific expression of the SMC1A gene in female Cornelia de Lange syndrome patients and healthy controls","volume":"9","author":"Parenti","year":"2014","journal-title":"Epigenetics"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Yuen, K.C., and Gerton, J.L. (2018). Taking cohesin and condensin in context. PLoS Genet., 14.","DOI":"10.1371\/journal.pgen.1007118"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Mannini, L., Cucco, F., Quarantotti, V., Amato, C., Tinti, M., Tana, L., Frattini, A., Delia, D., Krantz, I.D., and Jessberger, R. (2015). SMC1B is present in mammalian somatic cells and interacts with mitotic cohesin proteins. Sci. Rep., 5.","DOI":"10.1038\/srep18472"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1126\/science.1256917","article-title":"Closing the cohesin ring: Structure and function of its Smc3-kleisin interface","volume":"346","author":"Gligoris","year":"2014","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/nature24281","article-title":"Two independent modes of chromatin organization revealed by cohesin removal","volume":"551","author":"Schwarzer","year":"2017","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3002","DOI":"10.1093\/hmg\/ddy203","article-title":"Antioxidant treatment ameliorates phenotypic features of SMC1A-mutated Cornelia de Lange syndrome in vitro and in vivo","volume":"27","author":"Cukrov","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"144612","DOI":"10.1016\/j.gene.2020.144612","article-title":"The multiple facets of the SMC1A gene","volume":"743","author":"Musio","year":"2020","journal-title":"Gene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0378-1119(99)00021-9","article-title":"Cloning and characterization of mammalian SMC1 and SMC3 genes and proteins, components of the DNA recombination complexes RC-1","volume":"228","author":"Stursberg","year":"1999","journal-title":"Gene"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1177\/08830738221081244","article-title":"Further Characterization of SMC1A Loss of Function Epilepsy Distinct From Cornelia de Lange Syndrome","volume":"37","author":"Baranano","year":"2022","journal-title":"J. Child. Neurol."},{"key":"ref_11","unstructured":"Cooper, D.N., Ball, E.V., Stenson, P.D., Phillips, A.D., Evans, K., Heywood, S., Chapman, M., Hayden, M.J., Shiel, J., and Beynon, S. (2025, August 10). The Human Gene Mutation Database. Available online: http:\/\/www.hgmd.cf.ac.uk\/ac\/index.php."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Luppino, G., Wasniewska, M., Pepe, G., Morabito, L.A., Briuglia, S., Moschella, A., Franchina, F., Lugar\u00e0, C., Aversa, T., and Corica, D. (2025). Two Years of Growth Hormone Therapy in a Child with Severe Short Stature Due to Overlap Syndrome with a Novel SETD5 Gene Mutation: Case Report and Review of the Literature. Genes, 16.","DOI":"10.3390\/genes16080859"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1002\/humu.22430","article-title":"Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome","volume":"34","author":"Mannini","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.1002\/ajmg.a.38279","article-title":"Phenotypes and genotypes in individuals with SMC1A variants","volume":"173","author":"Huisman","year":"2017","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Yang, Y., Chen, L., Wang, Z., Ding, Y., and Liu, Y. (2025). A De Novo Frameshift Variant in SMC1A Causes Non-Classic Cornelia de Lange Syndrome with Epilepsy: A Case Report and Literature Review. Mol. Genet. Genomic Med., 13.","DOI":"10.1002\/mgg3.70058"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Pepe, G., Coco, R., Corica, D., Luppino, G., Morabito, L.A., Lugara, C., Abbate, T., Zirilli, G., Aversa, T., and Stagi, S. (2024). Endocrine disorders in Rett syndrome: A systematic review of the literature. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1477227"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Parmeggiani, L., Stanzial, F., Menna, E., Boni, E., Manzoni, F., Benedicenti, F., and Pellegrin, S. (2023). Early onset developmental and epileptic encephalopathy and Rett-like phenotype in a 15-year-old girl affected by Cornelia de Lange syndrome type 2 due to a SMC1A gene mutation. Epilepsy Behav. Rep., 24.","DOI":"10.1016\/j.ebr.2023.100634"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1111\/epi.13669","article-title":"Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: Detailed phenotyping of 10 new cases","volume":"58","author":"Symonds","year":"2017","journal-title":"Epilepsia"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Gibellato, E., Cianci, P., Mariani, M., Parma, B., Huisman, S., Smigiel, R., Bisgaard, A.M., Massa, V., Gervasini, C., and Moretti, A. (2024). SMC1A epilepsy syndrome: Clinical data from a large international cohort. Am. J. Med. Genet. A, 194.","DOI":"10.1002\/ajmg.a.63577"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"De Koninck, M., and Losada, A. (2016). Cohesin Mutations in Cancer. Cold Spring Harb. Perspect. Med., 6.","DOI":"10.1101\/cshperspect.a026476"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.tcb.2021.03.005","article-title":"Cohesin: Behind dynamic genome topology and gene expression reprogramming","volume":"31","author":"Wattendorf","year":"2021","journal-title":"Trends Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/s41586-020-2151-x","article-title":"Landscape of cohesin-mediated chromatin loops in the human genome","volume":"583","author":"Grubert","year":"2020","journal-title":"Nature"},{"key":"ref_23","first-page":"679","article-title":"Cohesin in 3D: Development, differentiation, and disease","volume":"39","author":"Losada","year":"2025","journal-title":"Genes. Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1111\/febs.16362","article-title":"Full circle: A brief history of cohesin and the regulation of gene expression","volume":"290","author":"Horsfield","year":"2023","journal-title":"FEBS J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/humu.21129","article-title":"Spectrum and consequences of SMC1A mutations: The unexpected involvement of a core component of cohesin in human disease","volume":"31","author":"Mannini","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3921","DOI":"10.1093\/nar\/gkh716","article-title":"SMC1 coordinates DNA double-strand break repair pathways","volume":"32","author":"Schar","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"749","DOI":"10.3892\/ol.2013.1116","article-title":"SMC1A knockdown induces growth suppression of human lung adenocarcinoma cells through G1\/S cell cycle phase arrest and apoptosis pathways in vitro","volume":"5","author":"Zhang","year":"2013","journal-title":"Oncol. Lett."},{"key":"ref_28","first-page":"862","article-title":"Knocking down SMC1A inhibits growth and leads to G2\/M arrest in human glioma cells","volume":"6","author":"Ma","year":"2013","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Di Nardo, M., Astigiano, S., Baldari, S., Pallotta, M.M., Porta, G., Pigozzi, S., Antonini, A., Emionite, L., Frattini, A., and Valli, R. (2024). The synergism of SMC1A cohesin gene silencing and bevacizumab against colorectal cancer. J. Exp. Clin. Cancer Res., 43.","DOI":"10.1186\/s13046-024-02976-2"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bozarth, X.L., Lopez, J., Fang, H., Lee-Eng, J., Duan, Z., and Deng, X. (2023). Phenotypes and Genotypes in Patients with SMC1A-Related Developmental and Epileptic Encephalopathy. Genes, 14.","DOI":"10.3390\/genes14040852"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/s41576-018-0031-0","article-title":"Diagnosis and management of Cornelia de Lange syndrome: First international consensus statement","volume":"19","author":"Kline","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Gil-Salvador, M., Latorre-Pellicer, A., Lucia-Campos, C., Arnedo, M., Darnaude, M.T., Diaz de Bustamante, A., Villares, R., Palma Milla, C., Puisac, B., and Musio, A. (2022). Case report: A novel case of parental mosaicism in SMC1A gene causes inherited Cornelia de Lange syndrome. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.993064"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Chen, J., Floyd, E.N., Dawson, D.S., and Rankin, S. (2023). Cornelia de Lange Syndrome mutations in SMC1A cause cohesion defects in yeast. Genetics, 225.","DOI":"10.1093\/genetics\/iyad159"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Costantino, L., Hsieh, T.S., Lamothe, R., Darzacq, X., and Koshland, D. (2020). Cohesin residency determines chromatin loop patterns. eLife, 9.","DOI":"10.7554\/eLife.59889"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Selivanovskiy, A.V., Molodova, M.N., Khrameeva, E.E., Ulianov, S.V., and Razin, S.V. (2025). Liquid condensates: A new barrier to loop extrusion?. Cell Mol. Life Sci., 82.","DOI":"10.1007\/s00018-024-05559-8"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Stortz, M., Presman, D.M., and Levi, V. (2024). Transcriptional condensates: A blessing or a curse for gene regulation?. Commun. Biol., 7.","DOI":"10.1038\/s42003-024-05892-5"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1074\/jbc.RA119.011099","article-title":"PDS5 proteins are required for proper cohesin dynamics and participate in replication fork protection","volume":"295","author":"Morales","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.tcb.2023.03.006","article-title":"NIPBL and cohesin: New take on a classic tale","volume":"33","author":"Losada","year":"2023","journal-title":"Trends Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s00412-007-0125-5","article-title":"Functional links between Drosophila Nipped-B and cohesin in somatic and meiotic cells","volume":"117","author":"Gause","year":"2008","journal-title":"Chromosoma"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1101\/gr.136507.111","article-title":"Cohesin regulates tissue-specific expression by stabilizing highly occupied cis-regulatory modules","volume":"22","author":"Faure","year":"2012","journal-title":"Genome Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/978-1-4939-0888-2_11","article-title":"The roles of cohesins in mitosis, meiosis, and human health and disease","volume":"1170","author":"Brooker","year":"2014","journal-title":"Methods Mol. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Sarogni, P., Palumbo, O., Servadio, A., Astigiano, S., D\u2019Alessio, B., Gatti, V., Cukrov, D., Baldari, S., Pallotta, M.M., and Aretini, P. (2019). Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer development. J. Exp. Clin. Cancer Res., 38.","DOI":"10.1186\/s13046-019-1116-0"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1038\/emboj.2012.60","article-title":"A unique role of cohesin-SA1 in gene regulation and development","volume":"31","author":"Remeseiro","year":"2012","journal-title":"EMBO J."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Liu, J., Zhang, Z., Bando, M., Itoh, T., Deardorff, M.A., Clark, D., Kaur, M., Tandy, S., Kondoh, T., and Rappaport, E. (2009). Transcriptional dysregulation in NIPBL and cohesin mutant human cells. PLoS Biol., 7.","DOI":"10.1371\/journal.pbio.1000119"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/ng.3229","article-title":"Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin","volume":"47","author":"Izumi","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1002\/ajmg.a.35381","article-title":"Germline mosaicism in Cornelia de Lange syndrome","volume":"158A","author":"Slavin","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Gardner, R.M., Sutherland, G.R., and Shaffer, L.G. (2012). Chromosome Abnormalities and Genetic Counseling, Oxford University Press (OUP).","DOI":"10.1093\/med\/9780195375336.001.0001"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1111\/cge.12729","article-title":"De novo loss-of-function mutations in X-linked SMC1A cause severe ID and therapy-resistant epilepsy in females: Expanding the phenotypic spectrum","volume":"90","author":"Jansen","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3076","DOI":"10.1002\/ajmg.a.37364","article-title":"Early-onset encephalopathy with epilepsy associated with a novel splice site mutation in SMC1A","volume":"167A","author":"Lebrun","year":"2015","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_50","first-page":"583","article-title":"Developmental and epileptic encephalopathy 85 caused by SMC1A gene truncating variation: 4 cases report and literature review","volume":"60","author":"Ye","year":"2022","journal-title":"Zhonghua Er Ke Za Zhi"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Generoso, S.F., Neguembor, M.V., Hershberg, E.A., Sadreyev, R.I., Kurimoto, K., Yabuta, Y., Ricci, R., Audergon, P., Bauer, M., and Saitou, M. (2023). Cohesin controls X chromosome structure remodeling and X-reactivation during mouse iPSC-reprogramming. Proc. Natl. Acad. Sci. USA, 120.","DOI":"10.1073\/pnas.2213810120"},{"key":"ref_52","unstructured":"Polin, R.A., Abman, S.H., Rowitch, D.H., Benitz, W.E., and Fox, W.W. (2017). 9-Epigenetics. Fetal and Neonatal Physiology, Elsevier. [5th ed.]."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Brand, B.A., Blesson, A.E., and Smith-Hicks, C.L. (2021). The Impact of X-Chromosome Inactivation on Phenotypic Expression of X-Linked Neurodevelopmental Disorders. Brain Sci., 11.","DOI":"10.3390\/brainsci11070904"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1002\/humu.9478","article-title":"Incidence and clinical features of X-linked Cornelia de Lange syndrome due to SMC1L1 mutations","volume":"28","author":"Borck","year":"2007","journal-title":"Hum. Mutat."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/pro.3943","article-title":"UCSF ChimeraX: Structure visualization for researchers, educators, and developers","volume":"30","author":"Pettersen","year":"2021","journal-title":"Protein Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1002\/ajmg.a.38228","article-title":"Genotype-phenotype correlations in Cornelia de Lange syndrome: Behavioral characteristics and changes with age","volume":"173","author":"Moss","year":"2017","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Moncayo, J.A., Ayala, I.N., Argudo, J.M., Aguirre, A.S., Parwani, J., Pachano, A., Ojeda, D., Cordova, S., Mora, M.G., and Tapia, C.M. (2022). Understanding Protein Protocadherin-19 (PCDH19) Syndrome: A Literature Review of the Pathophysiology. Cureus, 14.","DOI":"10.7759\/cureus.25808"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Tehrani Fateh, S., Mohammad Zadeh, N., Salehpour, S., Hashemi-Gorji, F., Omidi, A., Sadeghi, H., Mirfakhraie, R., Moghimi, P., Keyvanfar, S., and Mohammadi Sarvaleh, S. (2024). Comprehensive review and expanding the genetic landscape of Cornelia-de-Lange spectrum: Insights from novel mutations and skin biopsy in exome-negative cases. BMC Med. Genom., 17.","DOI":"10.1186\/s12920-024-01798-7"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Spagnoli, C., Fusco, C., and Pisani, F. (2021). Rett Syndrome Spectrum in Monogenic Developmental-Epileptic Encephalopathies and Epilepsies: A Review. Genes, 12.","DOI":"10.3390\/genes12081157"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.ejmg.2015.09.007","article-title":"Novel SMC1A frameshift mutations in children with developmental delay and epilepsy","volume":"58","author":"Goldstein","year":"2015","journal-title":"Eur. J. Med. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"R285","DOI":"10.1093\/hmg\/ddab221","article-title":"X-factors in human disease: Impact of gene content and dosage regulation","volume":"30","author":"Fang","year":"2021","journal-title":"Hum. Mol. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Berletch, J.B., Ma, W., Yang, F., Shendure, J., Noble, W.S., Disteche, C.M., and Deng, X. (2015). Escape from X inactivation varies in mouse tissues. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005079"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/ng1779","article-title":"X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations","volume":"38","author":"Musio","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_64","unstructured":"Deardorff, M.A., Noon, S.E., and Krantz, I.D. (2020). Cornelia de Lange Syndrome, University of Washington."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Vetri, L., Cali, F., Saccone, S., Vinci, M., Chiavetta, N.V., Carotenuto, M., Roccella, M., Costanza, C., and Elia, M. (2024). Whole Exome Sequencing as a First-Line Molecular Genetic Test in Developmental and Epileptic Encephalopathies. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25021146"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"a005322","DOI":"10.1101\/mcs.a005322","article-title":"A novel mosaic variant on SMC1A reported in buccal mucosa cells, albeit not in blood, of a patient with Cornelia de Lange-like presentation","volume":"6","author":"Malone","year":"2020","journal-title":"Cold Spring Harb. Mol. Case Stud."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Gil-Salvador, M., Trujillano, L., Lucia-Campos, C., Del Rincon, J., Pamplona, P., Arnedo, M., Puisac, B., Marcos-Alcalde, I., Gomez-Puertas, P., and Ramos, F.J. (2025). Postzygotic mosaicism in SMC1A and the first reported case of a female with Cornelia de Lange syndrome. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-07268-z"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"240","DOI":"10.5698\/1535-7597.18.4.240","article-title":"Modeling Pediatric Epilepsy Through iPSC-Based Technologies","volume":"18","author":"Simkin","year":"2018","journal-title":"Epilepsy Curr."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Zou, H., Zhang, Q., Liao, J., Zou, D., Hu, Z., Li, B., Chen, L., Wen, J., Zhao, X., and Zhang, V.W. (2024). Diagnostic efficiency of exome-based sequencing in pediatric patients with epilepsy. Front. Genet., 15.","DOI":"10.3389\/fgene.2024.1496411"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Crowgey, E.L., Mahajan, N., Wong, W.H., Gopalakrishnapillai, A., Barwe, S.P., Kolb, E.A., and Druley, T.E. (2020). Error-corrected sequencing strategies enable comprehensive detection of leukemic mutations relevant for diagnosis and minimal residual disease monitoring. BMC Med. Genom., 13.","DOI":"10.1186\/s12920-020-0671-8"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"i202","DOI":"10.1093\/bioinformatics\/bty264","article-title":"AmpUMI: Design and analysis of unique molecular identifiers for deep amplicon sequencing","volume":"34","author":"Clement","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Royer-Bertrand, B., Cisarova, K., Niel-Butschi, F., Mittaz-Crettol, L., Fodstad, H., and Superti-Furga, A. (2021). CNV Detection from Exome Sequencing Data in Routine Diagnostics of Rare Genetic Disorders: Opportunities and Limitations. Genes, 12.","DOI":"10.3390\/genes12091427"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1038\/s41431-020-0675-z","article-title":"Evaluation of CNV detection tools for NGS panel data in genetic diagnostics","volume":"28","author":"Castellanos","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jmoldx.2022.10.005","article-title":"Minigene Assay as an Effective Molecular Diagnostic Strategy in Determining the Pathogenicity of Noncanonical Splice-Site Variants in FLCN","volume":"25","author":"Zhang","year":"2023","journal-title":"J. Mol. Diagn."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Weng, O.Y., Li, Y., and Wang, L.Y. (2022). Modeling Epilepsy Using Human Induced Pluripotent Stem Cells-Derived Neuronal Cultures Carrying Mutations in Ion Channels and the Mechanistic Target of Rapamycin Pathway. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.810081"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/s41431-022-01232-5","article-title":"Comparing saliva and blood for the detection of mosaic genomic abnormalities that cause syndromic intellectual disability","volume":"31","author":"Francis","year":"2023","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.jmoldx.2023.04.003","article-title":"Detecting Low-Variant Allele Frequency Mosaic Pathogenic Variants of NF1, TSC2, and AKT3 Genes from Blood in Patients with Neurodevelopmental Disorders","volume":"25","author":"Kim","year":"2023","journal-title":"J. Mol. Diagn."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/gim.2013.92","article-title":"ACMG clinical laboratory standards for next-generation sequencing","volume":"15","author":"Rehm","year":"2013","journal-title":"Genet. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/ajmg.a.32016","article-title":"Descriptive epidemiology of Cornelia de Lange syndrome in Europe","volume":"146A","author":"Barisic","year":"2008","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1002\/humu.22761","article-title":"De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes","volume":"36","author":"Deardorff","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Balciuniene, J., DeChene, E.T., Akgumus, G., Romasko, E.J., Cao, K., Dubbs, H.A., Mulchandani, S., Spinner, N.B., Conlin, L.K., and Marsh, E.D. (2019). Use of a Dynamic Genetic Testing Approach for Childhood-Onset Epilepsy. JAMA Netw. Open, 2.","DOI":"10.1001\/jamanetworkopen.2019.2129"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1002\/humu.22685","article-title":"Hidden mutations in Cornelia de Lange syndrome limitations of sanger sequencing in molecular diagnostics","volume":"36","author":"Braunholz","year":"2015","journal-title":"Hum. Mutat."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/10\/1196\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:36:41Z","timestamp":1760362601000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/10\/1196"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,13]]},"references-count":82,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["genes16101196"],"URL":"https:\/\/doi.org\/10.3390\/genes16101196","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,13]]}}}