{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T15:12:51Z","timestamp":1767625971593,"version":"3.41.2"},"reference-count":31,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T00:00:00Z","timestamp":1724803200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["5K23NS107646\u201005","3K23NS107646\u201005S1","U01NS114312"],"award-info":[{"award-number":["5K23NS107646\u201005","3K23NS107646\u201005S1","U01NS114312"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["2T32MH112510"],"award-info":[{"award-number":["2T32MH112510"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010091","name":"International Foundation for CDKL5 Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010091","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018252","name":"LouLou Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018252","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006823","name":"Boston Children's Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006823","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pathogenic variants in the cyclin\u2010dependent kinase\u2010like 5 (<jats:italic>CDKL5<\/jats:italic>) gene are associated with CDKL5 deficiency disorder (CDD), a severe X\u2010linked developmental and epileptic encephalopathy. Deletions affecting the 5\u2032 untranslated region (UTR) of <jats:italic>CDKL5<\/jats:italic>, which involve the noncoding exon 1 and\/or alternatively spliced first exons (exons 1a\u2013e), are uncommonly reported. We describe genetic and phenotypic characteristics for 15 individuals with <jats:italic>CDKL5<\/jats:italic> partial gene deletions affecting the 5\u2032 UTR. All individuals presented characteristic features of CDD, including medically refractory infantile\u2010onset epilepsy, global developmental delay, and visual impairment. We performed RNA sequencing on fibroblast samples from three individuals with small deletions involving exons 1 and\/or 1a\/1b only. Results demonstrated reduced <jats:italic>CDKL5<\/jats:italic> mRNA expression with no evidence of expression from alternatively spliced first exons. Our study broadens the genotypic spectrum for CDD by adding to existing evidence that deletions affecting the 5\u2032 UTR of the <jats:italic>CDKL5<\/jats:italic> gene are associated with the disorder. We propose that smaller 5\u2032 UTR deletions may require additional molecular testing approaches such as RNA sequencing to determine pathogenicity.<\/jats:p>","DOI":"10.1002\/ajmg.a.63843","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T06:29:25Z","timestamp":1724912965000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Deletions in the <i>CDKL5<\/i> 5\u2032 untranslated region lead to CDKL5 deficiency disorder"],"prefix":"10.1002","volume":"197","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6719-6368","authenticated-orcid":false,"given":"Isabel","family":"Haviland","sequence":"first","affiliation":[{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralph D.","family":"Hector","sequence":"additional","affiliation":[{"name":"Simons Initiative for the Developing Brain &amp; Patrick Wild Centre, Centre for Discovery Brain Sciences University of Edinburgh  Edinburgh UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindsay C.","family":"Swanson","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aubrie Soucy","family":"Verran","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Department of Pediatrics Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"Sherrill","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Department of Pediatrics Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zo\u00eb","family":"Frazier","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"AnneMarie M.","family":"Denny","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology University of Saskatchewan  Saskatoon Saskatchewan Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenna","family":"Lucash","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1370-6195","authenticated-orcid":false,"given":"Holly A.","family":"Dubbs","sequence":"additional","affiliation":[{"name":"Division of Child Neurology, Children's Hospital of Philadelphia, Department of Neurology University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric D.","family":"Marsh","sequence":"additional","affiliation":[{"name":"Division of Child Neurology, Children's Hospital of Philadelphia, Department of Neurology University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith L.","family":"Weisenberg","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen","family":"Leonard","sequence":"additional","affiliation":[{"name":"Telethon Kids Institute The University of Western Australia  Perth Western Australia Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milena","family":"Crippa","sequence":"additional","affiliation":[{"name":"Research Laboratory of Medical Cytogenetics and Molecular Genetics IRCCS Istituto Auxologico Italiano  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Cogliati","sequence":"additional","affiliation":[{"name":"Research Laboratory of Medical Cytogenetics and Molecular Genetics IRCCS Istituto Auxologico Italiano  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5893-0193","authenticated-orcid":false,"given":"Silvia","family":"Russo","sequence":"additional","affiliation":[{"name":"Research Laboratory of Medical Cytogenetics and Molecular Genetics IRCCS Istituto Auxologico Italiano  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0127-7322","authenticated-orcid":false,"given":"Bernhard","family":"Suter","sequence":"additional","affiliation":[{"name":"Division of Child Neurology, Texas Children's Hospital, Departments of Neurology and Pediatrics Baylor College of Medicine  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajsekar","family":"Rajaraman","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology UCLA Mattel Children's Hospital  Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan K.","family":"Percy","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John M.","family":"Schreiber","sequence":"additional","affiliation":[{"name":"Division of Epilepsy, Neurophysiology, and Critical Care Neurology Children's National Hospital  Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4544-3724","authenticated-orcid":false,"given":"Scott","family":"Demarest","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Neurology, Precision Medicine Institute University of Colorado School of Medicine and Children's Hospital Colorado  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6969-5061","authenticated-orcid":false,"given":"Timothy A.","family":"Benke","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pharmacology and Neurology University of Colorado School of Medicine and Children's Hospital Colorado  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maya","family":"Chopra","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy W.","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Division of Genetics and Genomics, Department of Pediatrics Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5385-0119","authenticated-orcid":false,"given":"Heather E.","family":"Olson","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Division of Epilepsy and Clinical Neurophysiology Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,8,28]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.874695"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2023.04.015"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","unstructured":"Bahi\u2010Buisson N. Villeneuve N. Caietta E. Jacquette A. Maurey H. Matthijs G. Van Esch H. Delahaye A. Moncla A. Milh M. Zufferey F. Diebold B. & Bienvenu T. (2012). Recurrent mutations in the CDKL5 gene: Genotype\u2010phenotyperelationships.American Journal of Medical Genetics Part A 158A(7) 1612\u20131619. https:\/\/doi.org\/10.1002\/ajmg.a.35401","DOI":"10.1002\/ajmg.a.35401"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.30974"},{"key":"e_1_2_10_6_1","unstructured":"Benke T. A. Angione K. Downs J. Leonard H. Saldaris J. Marsh E. D. Olson H. &Haviland I.(2024).CDKL5 deficiency disorder. GeneReviews.https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK602610\/."},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/08830738211019284"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.15747"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2019.03.017"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16285"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000003352"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0157758"},{"key":"e_1_2_10_13_1","doi-asserted-by":"crossref","unstructured":"Hector R. D. Kalscheuer V. M. Hennig F. Leonard H. Downs J. Clarke A. Benke T.A. Armstrong J. Pineda M. Bailey M. E. S. & Cobb S. R. (2017). CDKL5 variants: Improving our understanding of a rare neurologic disorder.Neurology. Genetics 3(6) e200. https:\/\/doi.org\/10.1212\/NXG.0000000000000200","DOI":"10.1212\/NXG.0000000000000200"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-022-00921-5"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.12.015"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(22)00035-7"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2011.03174.x"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61504"},{"key":"e_1_2_10_20_1","doi-asserted-by":"crossref","unstructured":"MacKay C. I. Wong K. Demarest S. T. Benke T. A. Downs J. & Leonard H. (2021). Exploringgenotype\u2010phenotype relationships in the CDKL5 deficiency disorder using aninternational dataset.Clinical Genetics 99(1) 157\u2013165. https:\/\/doi.org\/10.1111\/cge.13862","DOI":"10.1111\/cge.13862"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-016-0418-y"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24302"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12803"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac1072"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2009.01194.x"},{"key":"e_1_2_10_26_1","doi-asserted-by":"crossref","unstructured":"Riggs E. R. Andersen E. F. Cherry A. M. Kantarci S. Kearney H. Patel A. Raca G. Ritter D. I. South S. T. Thorland E. C. Pineda\u2010Alvarez D. Aradhya S. & Martin C. L. (2020). 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). Genetics in Medicine: Official Journal of the American College of Medical Genetics 22(2) 245\u2013257. https:\/\/doi.org\/10.1038\/s41436\u2010019\u20100686\u20108","DOI":"10.1038\/s41436-019-0686-8"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.14908"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2019.02.015"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2017-310694"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1177\/08830738211019576"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1086\/426462"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2023.107231"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.63843","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T06:01:50Z","timestamp":1734069710000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.63843"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,28]]},"references-count":31,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1]]}},"alternative-id":["10.1002\/ajmg.a.63843"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.63843","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"type":"print","value":"1552-4825"},{"type":"electronic","value":"1552-4833"}],"subject":[],"published":{"date-parts":[[2024,8,28]]},"assertion":[{"value":"2024-05-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e63843"}}