{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:24:32Z","timestamp":1790713472906,"version":"4.1.0"},"reference-count":30,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,5,28]],"date-time":"2023-05-28T00:00:00Z","timestamp":1685232000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017638","name":"Ministry of Health of the Russian Federation","doi-asserted-by":"publisher","award":["122030300377-6"],"award-info":[{"award-number":["122030300377-6"]}],"id":[{"id":"10.13039\/501100017638","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Intellectual disability with developmental delay is the most common developmental disorder. However, this diagnosis is rarely associated with congenital cardiomyopathy. In the current report, we present the case of a patient suffering from dilated cardiomyopathy and developmental delay. Methods: Neurological pathology in a newborn was diagnosed immediately after birth, and the acquisition of psychomotor skills lagged behind by 3\u20134 months during the first year of life. WES analysis of the proband did not reveal a causal variant, so the search was extended to trio. Results: Trio sequencing revealed a de novo missense variant in the CAMK2D gene (p.Arg275His), that is, according to the OMIM database and available literature, not currently associated with any specific inborn disease. The expression of Ca2+\/calmodulin-dependent protein kinase II delta (CaMKII\u03b4) protein is known to be increased in the heart tissues from patients with dilated cardiomyopathy. The functional effect of the CaMKII\u03b4 Arg275His mutant was recently reported; however, no specific mechanism of its pathogenicity was proposed. A structural analysis and comparison of available three-dimensional structures of CaMKII\u03b4 confirmed the probable pathogenicity of the observed missense variant. Conclusions: We suggest that the CaMKII\u03b4 Arg275His variant is highly likely the cause of dilated cardiomyopathy and neurodevelopmental disorders.<\/jats:p>","DOI":"10.3390\/genes14061177","type":"journal-article","created":{"date-parts":[[2023,5,28]],"date-time":"2023-05-28T15:29:52Z","timestamp":1685287792000},"page":"1177","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["CAMK2D De Novo Missense Variant in Patient with Syndromic Neurodevelopmental Disorder: A Case Report"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2901-0539","authenticated-orcid":false,"given":"Ekaterina R.","family":"Tolmacheva","sequence":"first","affiliation":[{"name":"Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4383-7428","authenticated-orcid":false,"given":"Jekaterina","family":"Shubina","sequence":"additional","affiliation":[{"name":"Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0215-3636","authenticated-orcid":false,"given":"Taisiya O.","family":"Kochetkova","sequence":"additional","affiliation":[{"name":"Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubov\u2019 V.","family":"Ushakova","sequence":"additional","affiliation":[{"name":"Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina L.","family":"Bokerija","sequence":"additional","affiliation":[{"name":"Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1364-8418","authenticated-orcid":false,"given":"Grigory S.","family":"Vasiliev","sequence":"additional","affiliation":[{"name":"Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina V.","family":"Mikhaylovskaya","sequence":"additional","affiliation":[{"name":"Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina E.","family":"Atapina","sequence":"additional","affiliation":[{"name":"Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadezhda V.","family":"Zaretskaya","sequence":"additional","affiliation":[{"name":"Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gennady T.","family":"Sukhikh","sequence":"additional","affiliation":[{"name":"Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1884-1807","authenticated-orcid":false,"given":"Denis V.","family":"Rebrikov","sequence":"additional","affiliation":[{"name":"Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitriy Yu.","family":"Trofimov","sequence":"additional","affiliation":[{"name":"Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/S0140-6736(16)31713-5","article-title":"Dilated cardiomyopathy","volume":"390","author":"Weintraub","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1038\/s41569-019-0284-0","article-title":"Genetics of dilated cardiomyopathy: Practical implications for heart failure management","volume":"17","author":"Rosenbaum","year":"2020","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Yamada, T., and Nomura, S. (2021). Recent findings related to cardiomyopathy and genetics. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212522"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1111\/joim.12944","article-title":"Dilated cardiomyopathy: From epidemiologic to genetic phenotypes: A translational review of current literature","volume":"286","author":"Reichart","year":"2019","journal-title":"J. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13073-017-0410-8","article-title":"Genetics and genomics of dilated cardiomyopathy and systolic heart failure","volume":"9","author":"Tayal","year":"2017","journal-title":"Genome Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1016\/j.jacc.2021.08.039","article-title":"Association of Genetic Variants with Outcomes in Patients With Nonischemic Dilated Cardiomyopathy","volume":"78","author":"Ochoa","year":"2021","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.4330\/wjc.v6.i11.1156","article-title":"Importance of genetic evaluation and testing in pediatric cardiomyopathy","volume":"6","author":"Tariq","year":"2014","journal-title":"World J. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Lodato, V., Parlapiano, G., Cal\u00ec, F., Silvetti, M.S., Adorisio, R., Armando, M., El Hachem, M., Romanzo, A., Dionisi-Vici, C., and Digilio, M.C. (2022). Cardiomyopathies in Children and Systemic Disorders When Is It Useful to Look beyond the Heart?. J. Cardiovasc. Dev. Dis., 9.","DOI":"10.3390\/jcdd9020047"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.gene.2003.08.023","article-title":"Organization and evolution of multifunctional Ca2+\/CaM- dependent protein kinase genes","volume":"322","author":"Tombes","year":"2003","journal-title":"Gene"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1016\/j.ajhg.2017.10.003","article-title":"De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability","volume":"101","author":"Besnard","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1002\/acn3.528","article-title":"De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders","volume":"5","author":"Akita","year":"2018","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1038\/nn.4352","article-title":"Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability","volume":"19","author":"Lelieveld","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"eaaz0240","DOI":"10.1126\/scisignal.aaz0240","article-title":"Heterogeneity in human hippocampal CaMKII transcripts reveals allosteric hub-dependent regulation","volume":"13","author":"Sloutsky","year":"2020","journal-title":"Sci. Signal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1146\/annurev.biochem.71.110601.135410","article-title":"Neuronal Ca2+\/calmodulin-dependent protein kinase II: The role of structure and autoregulation in cellular function","volume":"71","author":"Hudmon","year":"2002","journal-title":"Annu. Rev. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e117","DOI":"10.1016\/j.ddmec.2010.07.005","article-title":"Ca2+\/calmodulin-dependent protein kinase II in heart failure","volume":"7","author":"Schulman","year":"2010","journal-title":"Drug Discov. Today Dis. Mech."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.1007\/s00018-008-8086-2","article-title":"Ca2+\/calmodulin-dependent protein kinases","volume":"65","author":"Swulius","year":"2008","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Rellos, P., Pike, A.C., Niesen, F.H., Salah, E., Lee, W.H., Von Delft, F., and Knapp, S. (2010). Structure of the CaMKII\u03b4\/calmodulin complex reveals the molecular mechanism of CamKII kinase activation. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000426"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"26199","DOI":"10.1074\/jbc.274.37.26199","article-title":"Structural examination of autoregulation of multifunctional calcium\/calmodulin-dependent protein kinase II","volume":"274","author":"Yang","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_19","unstructured":"Theses Dissertations, M., and Dunn, M.J. (2022). Determining CaMKII Variant Activities and Their Roles in Human Disease. [Master\u2019s Thesis, University of Massachusetts Amherst]."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2714","DOI":"10.1002\/elps.1150181505","article-title":"SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling","volume":"21","author":"Guex","year":"1997","journal-title":"Electrophoresis"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"W395","DOI":"10.1093\/nar\/gkw395","article-title":"RCD+: Fast loop modeling server","volume":"44","author":"Li","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual Molecular Dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.sbi.2013.04.002","article-title":"Structural studies on the regulation of Ca2+\/calmodulin dependent protein kinase II","volume":"23","author":"Stratton","year":"2013","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1007\/s12035-018-1144-3","article-title":"Sustained CaMKII Delta Gene Expression Is Specifically Required for Long-Lasting Memories in Mice","volume":"56","author":"Zalcman","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1161\/CIRCRESAHA.111.243956","article-title":"Calmodulin-dependent protein kinase II: Linking heart failure and arrhythmias","volume":"110","author":"Swaminathan","year":"2012","journal-title":"Circ. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3389\/fphar.2014.00015","article-title":"CaMKIIdelta subtypes: Localization and function","volume":"5","author":"Gray","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1172\/JCI39262","article-title":"CaMKII and a failing strategy for growth in heart","volume":"119","author":"Anderson","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.brainresbull.2021.03.014","article-title":"Role of calcium\/calmodulin-dependent kinase 2 in neurodevelopmental disorders","volume":"171","year":"2021","journal-title":"Brain Res. Bull."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1161\/01.RES.0000069686.31472.C5","article-title":"The \u03b4c isoform of CaMKII is activated in cardiac hypertrophy and induces dilated cardiomyopathy and heart failure","volume":"92","author":"Zhang","year":"2003","journal-title":"Circ. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"695401","DOI":"10.3389\/fphar.2021.695401","article-title":"CaMKII Inhibition is a Novel Therapeutic Strategy to Prevent Diabetic Cardiomyopathy","volume":"12","author":"Veitch","year":"2021","journal-title":"Front. Pharmacol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/6\/1177\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:43:58Z","timestamp":1760125438000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/6\/1177"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,28]]},"references-count":30,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["genes14061177"],"URL":"https:\/\/doi.org\/10.3390\/genes14061177","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,28]]}}}