{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T04:19:28Z","timestamp":1783743568884,"version":"3.55.0"},"reference-count":11,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T00:00:00Z","timestamp":1736726400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T00:00:00Z","timestamp":1736726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universit\u00e4tsklinikum Carl Gustav Carus Dresden an der Technischen Universit\u00e4t Dresden"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Epigenet"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Autosomal dominant <jats:italic>CDK13<\/jats:italic>-related disease is characterized by congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD). Heterozygous pathogenic variants, particularly missense variants in the kinase domain, have previously been described as disease causing. Using the determination of a methylation pattern and comparison with an established episignature, we reveal the first hypomorphic variant in the kinase domain of <jats:italic>CDK13,<\/jats:italic> leading to a never before described autosomal recessive form of CHDFIDD in a boy with characteristic features. This highlights the utility of episignatures in variant interpretation, as well as a potential novel diagnostic approach in unsolved cases or for disease prognosis.<\/jats:p>","DOI":"10.1186\/s13148-024-01807-7","type":"journal-article","created":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T03:51:06Z","timestamp":1736740266000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Validation of a hypomorphic variant in CDK13 as the cause of CHDFIDD with autosomal recessive inheritance through determination of an episignature"],"prefix":"10.1186","volume":"17","author":[{"given":"Jan","family":"Fischer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari\u00eblle","family":"Alders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel M. A. M.","family":"Mannens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Genevieve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Hackmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelin","family":"Schr\u00f6ck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bekim","family":"Sadikovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Porrmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,13]]},"reference":[{"key":"1807_CR1","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1186\/s13073-017-0463-8","volume":"9","author":"BL Bostwick","year":"2017","unstructured":"Bostwick BL, McLean S, Posey JE, Streff HE, Gripp KW, Blesson A, et al. Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders. Genome Med. 2017;9:73.","journal-title":"Genome Med"},{"key":"1807_CR2","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1136\/jmedgenet-2017-104620","volume":"55","author":"MJ Hamilton","year":"2018","unstructured":"Hamilton MJ, Caswell RC, Canham N, Cole T, Firth HV, Foulds N, et al. Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability. J Med Genet. 2018;55:28\u201338.","journal-title":"J Med Genet"},{"key":"1807_CR3","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1016\/j.celrep.2015.12.025","volume":"14","author":"AK Greifenberg","year":"2016","unstructured":"Greifenberg AK, H\u00f6nig D, Pilarova K, D\u00fcster R, Bartholomeeusen K, B\u00f6sken CA, et al. Structural and functional analysis of the Cdk13\/cyclin K complex. Cell Rep. 2016;14:320\u201331.","journal-title":"Cell Rep"},{"key":"1807_CR4","doi-asserted-by":"publisher","first-page":"17122","DOI":"10.1038\/srep17122","volume":"5","author":"SE Dixon-Clarke","year":"2015","unstructured":"Dixon-Clarke SE, Elkins JM, Cheng S-WG, Morin GB, Bullock AN. Structures of the CDK12\/CycK complex with AMP-PNP reveal a flexible C-terminal kinase extension important for ATP binding. Sci Rep. 2015;5:17122.","journal-title":"Sci Rep"},{"key":"1807_CR5","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1016\/j.gim.2021.12.016","volume":"24","author":"F Rouxel","year":"2022","unstructured":"Rouxel F, Relator R, Kerkhof J, McConkey H, Levy M, Dias P, et al. CDK13-related disorder: report of a series of 18 previously unpublished individuals and description of an epigenetic signature. Genet Med. 2022;24:1096\u2013107.","journal-title":"Genet Med"},{"issue":"3","key":"1807_CR6","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1016\/j.ajhg.2020.01.019","volume":"106","author":"E Aref-Eshghi","year":"2020","unstructured":"Aref-Eshghi E, Kerkhof J, Pedro VP, Barat-Houari M, Ruiz-Pallares N, Andrau JC, Sadikovic B. Evaluation of DNA methylation Episignatures for diagnosis and phenotype correlations in 42 Mendelian neurodevelopmental disorders. Am J Human Genet. 2020;106(3):356\u201370.","journal-title":"Am J Human Genet"},{"key":"1807_CR7","volume":"5","author":"L van der Laan","year":"2024","unstructured":"van der Laan L, Lauffer P, Rooney K, Silva A, Haghshenas S, Relator R, et al. DNA methylation episignature and comparative epigenomic profiling for Pitt-Hopkins syndrome caused by TCF4 variants. HGG Adv. 2024;5: 100289.","journal-title":"HGG Adv"},{"key":"1807_CR8","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2024.101075","volume":"26","author":"J Kerkhof","year":"2024","unstructured":"Kerkhof J, Rastin C, Levy MA, Relator R, McConkey H, Demain L, et al. Diagnostic utility and reporting recommendations for clinical DNA methylation episignature testing in genetically undiagnosed rare diseases. Genet Med. 2024;26: 101075.","journal-title":"Genet Med"},{"key":"1807_CR9","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.210381","volume":"12","author":"R D\u00fcster","year":"2022","unstructured":"D\u00fcster R, Ji Y, Pan K-T, Urlaub H, Geyer M. Functional characterization of the human Cdk10\/cyclin Q complex. Open Biol. 2022;12: 210381.","journal-title":"Open Biol"},{"key":"1807_CR10","doi-asserted-by":"publisher","first-page":"1470","DOI":"10.1093\/nar\/gkaa1289","volume":"49","author":"M Roli\u0144ski","year":"2021","unstructured":"Roli\u0144ski M, Pietro MN, Aksu ME, Fordyce Martin SL, Brambilla A, Kunath N, et al. Loss of Mediator complex subunit 13 (MED13) promotes resistance to alkylation through cyclin D1 upregulation. Nucleic Acids Res. 2021;49:1470\u201384.","journal-title":"Nucleic Acids Res"},{"key":"1807_CR11","doi-asserted-by":"publisher","first-page":"1867","DOI":"10.1016\/j.ajhg.2022.08.014","volume":"109","author":"S Choufani","year":"2022","unstructured":"Choufani S, McNiven V, Cytrynbaum C, Jangjoo M, Adam MP, Bjornsson HT, et al. An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome. Am J Hum Genet. 2022;109:1867\u201384.","journal-title":"Am J Hum Genet"}],"container-title":["Clinical Epigenetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13148-024-01807-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13148-024-01807-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13148-024-01807-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T15:42:48Z","timestamp":1736782968000},"score":1,"resource":{"primary":{"URL":"https:\/\/clinicalepigeneticsjournal.biomedcentral.com\/articles\/10.1186\/s13148-024-01807-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,13]]},"references-count":11,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1807"],"URL":"https:\/\/doi.org\/10.1186\/s13148-024-01807-7","relation":{},"ISSN":["1868-7083"],"issn-type":[{"value":"1868-7083","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,13]]},"assertion":[{"value":"18 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 December 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 January 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Consent for publication was obtained from all participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Ethics approval for the study was obtained through the local ethics committee at the Technical University Dresden (reference number: EK 273072018). Consent to participate in the study was obtained from all individuals or their legal guardian.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"B.S. is an employee and shareholder of EpiSign, Inc., a biotech firm involved in commercial application of EpiSign technology.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"5"}}