{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T15:02:40Z","timestamp":1775746960546,"version":"3.50.1"},"reference-count":31,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T00:00:00Z","timestamp":1659916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Ministry of Health-ISCIII Fondo de Investigaci\u00f3n Sanitaria (FIS)","award":["PI19\/01860"],"award-info":[{"award-number":["PI19\/01860"]}]},{"name":"Spanish Ministry of Health-ISCIII Fondo de Investigaci\u00f3n Sanitaria (FIS)","award":["B32_17R\/B32_20R"],"award-info":[{"award-number":["B32_17R\/B32_20R"]}]},{"name":"Spanish Ministry of Health-ISCIII Fondo de Investigaci\u00f3n Sanitaria (FIS)","award":["RTI2018-094434-B-I00"],"award-info":[{"award-number":["RTI2018-094434-B-I00"]}]},{"name":"Spanish Ministry of Health-ISCIII Fondo de Investigaci\u00f3n Sanitaria (FIS)","award":["PI20\/01767"],"award-info":[{"award-number":["PI20\/01767"]}]},{"name":"Spanish Ministry of Health-ISCIII Fondo de Investigaci\u00f3n Sanitaria (FIS)","award":["No. FIS PI18\/000687"],"award-info":[{"award-number":["No. FIS PI18\/000687"]}]},{"name":"Diputaci\u00f3n General de Arag\u00f3n-FEDER: European Social Fund","award":["PI19\/01860"],"award-info":[{"award-number":["PI19\/01860"]}]},{"name":"Diputaci\u00f3n General de Arag\u00f3n-FEDER: European Social Fund","award":["B32_17R\/B32_20R"],"award-info":[{"award-number":["B32_17R\/B32_20R"]}]},{"name":"Diputaci\u00f3n General de Arag\u00f3n-FEDER: European Social Fund","award":["RTI2018-094434-B-I00"],"award-info":[{"award-number":["RTI2018-094434-B-I00"]}]},{"name":"Diputaci\u00f3n General de Arag\u00f3n-FEDER: European Social Fund","award":["PI20\/01767"],"award-info":[{"award-number":["PI20\/01767"]}]},{"name":"Diputaci\u00f3n General de Arag\u00f3n-FEDER: European Social Fund","award":["No. FIS PI18\/000687"],"award-info":[{"award-number":["No. FIS PI18\/000687"]}]},{"name":"a Predoctoral Fellowship from the MH-ISCIII","award":["PI19\/01860"],"award-info":[{"award-number":["PI19\/01860"]}]},{"name":"a Predoctoral Fellowship from the MH-ISCIII","award":["B32_17R\/B32_20R"],"award-info":[{"award-number":["B32_17R\/B32_20R"]}]},{"name":"a Predoctoral Fellowship from the MH-ISCIII","award":["RTI2018-094434-B-I00"],"award-info":[{"award-number":["RTI2018-094434-B-I00"]}]},{"name":"a Predoctoral Fellowship from the MH-ISCIII","award":["PI20\/01767"],"award-info":[{"award-number":["PI20\/01767"]}]},{"name":"a Predoctoral Fellowship from the MH-ISCIII","award":["No. FIS PI18\/000687"],"award-info":[{"award-number":["No. FIS PI18\/000687"]}]},{"name":"Spanish Instituto de Salud Carlos III","award":["PI19\/01860"],"award-info":[{"award-number":["PI19\/01860"]}]},{"name":"Spanish Instituto de Salud Carlos III","award":["B32_17R\/B32_20R"],"award-info":[{"award-number":["B32_17R\/B32_20R"]}]},{"name":"Spanish Instituto de Salud Carlos III","award":["RTI2018-094434-B-I00"],"award-info":[{"award-number":["RTI2018-094434-B-I00"]}]},{"name":"Spanish Instituto de Salud Carlos III","award":["PI20\/01767"],"award-info":[{"award-number":["PI20\/01767"]}]},{"name":"Spanish Instituto de Salud Carlos III","award":["No. FIS PI18\/000687"],"award-info":[{"award-number":["No. FIS PI18\/000687"]}]},{"name":"Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-funded","award":["PI19\/01860"],"award-info":[{"award-number":["PI19\/01860"]}]},{"name":"Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-funded","award":["B32_17R\/B32_20R"],"award-info":[{"award-number":["B32_17R\/B32_20R"]}]},{"name":"Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-funded","award":["RTI2018-094434-B-I00"],"award-info":[{"award-number":["RTI2018-094434-B-I00"]}]},{"name":"Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-funded","award":["PI20\/01767"],"award-info":[{"award-number":["PI20\/01767"]}]},{"name":"Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-funded","award":["No. FIS PI18\/000687"],"award-info":[{"award-number":["No. FIS PI18\/000687"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Cornelia de Lange syndrome (CdLS) is a multisystemic genetic disorder characterized by distinctive facial features, growth retardation, and intellectual disability, as well as various systemic conditions. It is caused by genetic variants in genes related to the cohesin complex. Single-nucleotide variations are the best-known genetic cause of CdLS; however, copy number variants (CNVs) clearly underlie a substantial proportion of cases of the syndrome. The NIPBL gene was thought to be the locus within which clinically relevant CNVs contributed to CdLS. However, in the last few years, pathogenic CNVs have been identified in other genes such as HDAC8, RAD21, and SMC1A. Here, we studied an affected girl presenting with a classic CdLS phenotype heterozygous for a de novo ~32 kbp intragenic duplication affecting exon 10 of HDAC8. Molecular analyses revealed an alteration in the physiological splicing that included a 96 bp insertion between exons 9 and 10 of the main transcript of HDAC8. The aberrant transcript was predicted to generate a truncated protein whose accessibility to the active center was restricted, showing reduced ease of substrate entry into the mutated enzyme. Lastly, we conclude that the duplication is responsible for the patient\u2019s phenotype, highlighting the contribution of CNVs as a molecular cause underlying CdLS.<\/jats:p>","DOI":"10.3390\/genes13081413","type":"journal-article","created":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T21:09:18Z","timestamp":1659992958000},"page":"1413","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Novel Intragenic Duplication in the HDAC8 Gene Underlying a Case of Cornelia de Lange Syndrome"],"prefix":"10.3390","volume":"13","author":[{"given":"Cristina","family":"Lucia-Campos","sequence":"first","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of Medicine, Universidad de Zaragoza, CIBERER-GCV02 and IIS-Aragon, E-50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"Valenzuela","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Genetics Hospital Vall d\u2019Hebron, E-08035 Barcelona, Spain"},{"name":"Medicine Genetics Group, Vall Hebron Research Institute, E-08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4703-6620","authenticated-orcid":false,"given":"Ana","family":"Latorre-Pellicer","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of Medicine, Universidad de Zaragoza, CIBERER-GCV02 and IIS-Aragon, E-50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Ros-Pardo","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa, CBMSO (CSIC-UAM), Molecular Modeling Group, E-28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Gil-Salvador","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of Medicine, Universidad de Zaragoza, CIBERER-GCV02 and IIS-Aragon, E-50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9962-2157","authenticated-orcid":false,"given":"Mar\u00eda","family":"Arnedo","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of Medicine, Universidad de Zaragoza, CIBERER-GCV02 and IIS-Aragon, E-50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0170-7326","authenticated-orcid":false,"given":"Beatriz","family":"Puisac","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of Medicine, Universidad de Zaragoza, CIBERER-GCV02 and IIS-Aragon, E-50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neus","family":"Castells","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Genetics Hospital Vall d\u2019Hebron, E-08035 Barcelona, Spain"},{"name":"Medicine Genetics Group, Vall Hebron Research Institute, E-08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Plaja","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Genetics Hospital Vall d\u2019Hebron, E-08035 Barcelona, Spain"},{"name":"Medicine Genetics Group, Vall Hebron Research Institute, E-08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Tenes","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Genetics Hospital Vall d\u2019Hebron, E-08035 Barcelona, Spain"},{"name":"Medicine Genetics Group, Vall Hebron Research Institute, E-08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivon","family":"Cusc\u00f3","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Genetics Hospital Vall d\u2019Hebron, E-08035 Barcelona, Spain"},{"name":"Medicine Genetics Group, Vall Hebron Research Institute, E-08035 Barcelona, Spain"},{"name":"Department of Genetics, Hospital Sant Pau, E-08041 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3028-6156","authenticated-orcid":false,"given":"Laura","family":"Trujillano","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Genetics Hospital Vall d\u2019Hebron, E-08035 Barcelona, Spain"},{"name":"Medicine Genetics Group, Vall Hebron Research Institute, E-08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5732-2209","authenticated-orcid":false,"given":"Feliciano J.","family":"Ramos","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics, Department of Paediatrics, Service of Paediatrics, Hospital Cl\u00ednico Universitario Lozano Blesa, School of Medicine, Universidad de Zaragoza, CIBERER-GCV02 and IIS-Aragon, E-50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduardo F.","family":"Tizzano","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Genetics Hospital Vall d\u2019Hebron, E-08035 Barcelona, Spain"},{"name":"Medicine Genetics Group, Vall Hebron Research Institute, E-08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3131-729X","authenticated-orcid":false,"given":"Paulino","family":"G\u00f3mez-Puertas","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa, CBMSO (CSIC-UAM), Molecular Modeling Group, E-28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3203-6254","authenticated-orcid":false,"given":"Juan","family":"Pi\u00e9","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of Medicine, Universidad de Zaragoza, CIBERER-GCV02 and IIS-Aragon, E-50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,8]]},"reference":[{"key":"ref_1","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_2","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_3","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s00439-020-02138-2","article-title":"Delineation of phenotypes and genotypes related to cohesin structural protein RAD21","volume":"139","author":"Krab","year":"2020","journal-title":"Hum. Genet."},{"key":"ref_4","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_5","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_6","doi-asserted-by":"crossref","first-page":"2888","DOI":"10.1093\/hmg\/ddu002","article-title":"Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance","volume":"23","author":"Kaiser","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1111\/cge.12717","article-title":"Expanding the clinical spectrum of the \u2018HDAC8 -phenotype\u2019\u2014Implications for molecular diagnostics, counseling and risk prediction: Expanding the clinical spectrum of the \u2018HDAC8 -phenotype\u2019","volume":"89","author":"Parenti","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e1826","DOI":"10.1002\/mgg3.1826","article-title":"Things are not always what they seem: From Cornelia de Lange to KBG phenotype in a girl with genetic variants in NIPBL and ANKRD11","volume":"9","author":"Ascaso","year":"2021","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15459","DOI":"10.1038\/s41598-021-94958-z","article-title":"Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood","volume":"11","author":"Parenti","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1038\/ejhg.2012.7","article-title":"Intragenic and large NIPBL rearrangements revealed by MLPA in Cornelia de Lange patients","volume":"20","author":"Russo","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1111\/cge.12194","article-title":"Could a patient with SMC1A duplication be classified as a human cohesinopathy?: Could a patient with SMC1A duplication be classified as a human cohesinopathy?","volume":"85","author":"Remeseiro","year":"2014","journal-title":"Clin. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/s10038-017-0387-6","article-title":"Molecular characterization of HDAC8 deletions in individuals with atypical Cornelia de Lange syndrome","volume":"63","author":"Helgeson","year":"2018","journal-title":"J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"144966","DOI":"10.1016\/j.gene.2020.144966","article-title":"Cohesin subunit RAD21: From biology to disease","volume":"758","author":"Cheng","year":"2020","journal-title":"Gene"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Latorre-Pellicer, A., Ascaso, \u00c1., Trujillano, L., Gil-Salvador, M., Arnedo, M., Lucia-Campos, C., Anto\u00f1anzas-P\u00e9rez, R., Marcos-Alcalde, I., Parenti, I., and Bueno-Lozano, G. (2020). Evaluating Face2Gene as a Tool to Identify Cornelia de Lange Syndrome by Facial Phenotypes. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21031042"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1097\/GIM.0b013e3182217a3a","article-title":"American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants","volume":"13","author":"Kearney","year":"2011","journal-title":"Genet. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41436-019-0686-8","article-title":"Technical standards for the interpretation and reporting of constitutional copy-number variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)","volume":"22","author":"Riggs","year":"2020","journal-title":"Genet. 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Graph."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/nature11316","article-title":"HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle","volume":"489","author":"Deardorff","year":"2012","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/jhg.2014.68","article-title":"A commentary on exome sequencing identifies a de novo mutation in HDAC8 associated with Cornelia de Lange syndrome","volume":"59","author":"Sun","year":"2014","journal-title":"J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/jhg.2014.113","article-title":"Exome sequencing identifies a de novo mutation in HDAC8 associated with Cornelia de Lange syndrome","volume":"60","author":"Feng","year":"2015","journal-title":"J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1159\/000491613","article-title":"A Functional Mutation in HDAC8 Gene as Novel Diagnostic Marker for Cornelia De Lange Syndrome","volume":"47","author":"Gao","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1097\/MCD.0000000000000277","article-title":"Novel variant in HDAC8 gene resulting in the severe Cornelia de Lange phenotype","volume":"28","author":"Murcia","year":"2019","journal-title":"Clin. Dysmorphol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e1612","DOI":"10.1002\/mgg3.1612","article-title":"A novel de novo HDAC8 missense mutation causing Cornelia de Lange syndrome","volume":"9","author":"Mio","year":"2021","journal-title":"Mol. Genet. Genom. 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Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6501","DOI":"10.1021\/acs.biochem.5b00881","article-title":"Biochemical and Structural Characterization of HDAC8 Mutants Associated with Cornelia de Lange Syndrome Spectrum Disorders","volume":"54","author":"Decroos","year":"2015","journal-title":"Biochemistry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1002\/pro.3030","article-title":"Structural aspects of HDAC8 mechanism and dysfunction in Cornelia de Lange syndrome spectrum disorders: Structural Aspects of HDAC8 Mechanism","volume":"25","author":"Deardorff","year":"2016","journal-title":"Protein Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"107681","DOI":"10.1016\/j.jsb.2020.107681","article-title":"Structural analysis of histone deacetylase 8 mutants associated with Cornelia de Lange Syndrome spectrum disorders","volume":"213","author":"Osko","year":"2021","journal-title":"J. Struct. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6718","DOI":"10.1021\/acs.biochem.6b01014","article-title":"Structural and Functional Influence of the Glycine-Rich Loop G 302 GGGY on the Catalytic Tyrosine of Histone Deacetylase 8","volume":"55","author":"Porter","year":"2016","journal-title":"Biochemistry"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/8\/1413\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:05:58Z","timestamp":1760141158000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/8\/1413"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,8]]},"references-count":31,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["genes13081413"],"URL":"https:\/\/doi.org\/10.3390\/genes13081413","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,8]]}}}