{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:15:13Z","timestamp":1788430513507,"version":"build-2803163510"},"reference-count":20,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T00:00:00Z","timestamp":1788048000000},"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>Background: PRKD1-related congenital heart defects and ectodermal dysplasia syndrome (CHDED) is a rare multisystem developmental disorder caused by heterozygous gain-of-function variants in PRKD1. Reported phenotypes include congenital heart defects, ectodermal abnormalities, limb anomalies, and neurodevelopmental impairment, while vascular manifestations remain poorly characterized. We report an adult patient with a de novo PRKD1 variant and bilateral carotid artery dissections. Methods: Clinical, cardiovascular, neurological, and genetic evaluations were performed, including SNP-microarray and trio whole-exome sequencing with additional analysis of genes associated with heritable thoracic aortic and connective tissue disorders. Results: The patient was diagnosed at 35 years of age with a de novo PRKD1 c.1808G&gt;A p.(Arg603His) variant. He had childhood-onset congenital heart disease, ectodermal and skeletal abnormalities, hearing impairment, infertility, and learning difficulties. In adulthood, he developed bilateral carotid artery dissections and mild aortic dilatation. No additional pathogenic or likely pathogenic variants were identified in the evaluated connective tissue and heritable aortic disease genes. The PRKD1 variant was absent or extremely rare in population databases and had supporting functional evidence for a gain-of-function effect. Conclusions: This case raises the possibility of a previously unrecognized vascular manifestation of PRKD1-related CHDED. Although a biological association is plausible, causality cannot be established from a single case. Further clinical and functional studies are needed to determine whether vascular fragility is a recurrent feature of PRKD1-related disease. This case also highlights the importance of considering rare genetic syndromes in patients with unexplained arteriopathy and congenital heart disease.<\/jats:p>","DOI":"10.3390\/genes17091048","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T02:08:58Z","timestamp":1788142138000},"page":"1048","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Expanding the Phenotypic Spectrum of PRKD1 Gain-of-Function Syndrome: Congenital Heart Disease, Bilateral Carotid Dissections, and Ectodermal Dysplasia in an Adult Patient"],"prefix":"10.3390","volume":"17","author":[{"given":"Pedram","family":"Kharaziha","sequence":"first","affiliation":[{"name":"Clinical Department of Clinical Genetics, Region \u00d6sterg\u00f6tland, 58185 Link\u00f6ping, Sweden"},{"name":"Department of Biomedical and Clinical Sciences, Link\u00f6ping University, 58185 Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1124-2729","authenticated-orcid":false,"given":"Klara","family":"Junker","sequence":"additional","affiliation":[{"name":"Clinical Department of Precision Medicine Laboratory, Region \u00d6sterg\u00f6tland, 58185 Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josefine","family":"\u00c5hsberg","sequence":"additional","affiliation":[{"name":"Clinical Department of Precision Medicine Laboratory, Region \u00d6sterg\u00f6tland, 58185 Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8988-5591","authenticated-orcid":false,"given":"Antheia","family":"Kissopoulou","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, County Council of J\u00f6nk\u00f6ping, 58185 Link\u00f6ping, Sweden"},{"name":"Department of Health, Medicine and Caring Sciences, Link\u00f6ping University, 58185 Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ren, B. (2016). Protein Kinase D1 Signaling in Angiogenic Gene Expression and VEGF-Mediated Angiogenesis. Front. Cell Dev. Biol., 4.","DOI":"10.3389\/fcell.2016.00037"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1042\/BJ20101188","article-title":"Unique functions for protein kinase D1 and protein kinase D2 in mammalian cells","volume":"432","author":"Matthews","year":"2010","journal-title":"Biochem. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"13205","DOI":"10.1074\/jbc.R500002200","article-title":"Protein kinase D signaling","volume":"280","author":"Rozengurt","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"14590","DOI":"10.1074\/jbc.M800264200","article-title":"Protein kinase D-dependent phosphorylation and nuclear export of histone deacetylase 5 mediates vascular endothelial growth factor-induced gene expression and angiogenesis","volume":"283","author":"Ha","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"22609","DOI":"10.1074\/jbc.M112.379719","article-title":"Regulatory domain determinants that control PKD1 activity","volume":"287","author":"Rybin","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1124\/molpharm.121.000341","article-title":"Decoding the Cardiac Actions of Protein Kinase D Isoforms","volume":"100","author":"Steinberg","year":"2021","journal-title":"Mol. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhang, X., Connelly, J., Chao, Y., and Wang, Q.J. (2021). Multifaceted Functions of Protein Kinase D in Pathological Processes and Human Diseases. Biomolecules, 11.","DOI":"10.3390\/biom11030483"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1073\/pnas.0712265105","article-title":"Requirement of protein kinase D1 for pathological cardiac remodeling","volume":"105","author":"Fielitz","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8572","DOI":"10.1073\/pnas.91.18.8572","article-title":"Molecular cloning and characterization of protein kinase D: A target for diacylglycerol and phorbol esters with a distinctive catalytic domain","volume":"91","author":"Valverde","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3310","DOI":"10.1074\/jbc.M008719200","article-title":"Molecular Cloning and Characterization of the Human Protein Kinase D2","volume":"276","author":"Sturany","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0167-4889(99)00040-3","article-title":"PKCnu, a new member of the protein kinase C family, composes a fourth subfamily with PKCmu","volume":"1450","author":"Hayashi","year":"1999","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3757","DOI":"10.2741\/2349","article-title":"Protein kinase D1: A protein of emerging translational interest","volume":"12","author":"Jaggi","year":"2007","journal-title":"Front. Biosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"104942","DOI":"10.1016\/j.ejmg.2024.104942","article-title":"PRKD1-related telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly syndrome: Case report and review of the literature","volume":"69","author":"Leduc","year":"2024","journal-title":"Eur. J. Med. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1136\/jmedgenet-2019-106564","article-title":"Telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly syndrome is caused by de novo mutations in protein kinase D1","volume":"58","author":"Alter","year":"2021","journal-title":"J. Med. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6500","DOI":"10.1074\/jbc.M110.208058","article-title":"Protein kinase D isoforms are activated in an agonist-specific manner in cardiomyocytes","volume":"286","author":"Guo","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1111\/joa.14033","article-title":"Effect of deletion of the protein kinase PRKD1 on development of the mouse embryonic heart","volume":"245","author":"Wilsdon","year":"2024","journal-title":"J. Anat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/ng.3627","article-title":"Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing","volume":"48","author":"Sifrim","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Digilio, M.C., and Marino, B. (2016). What Is New in Genetics of Congenital Heart Defects?. Front. Pediatr., 4.","DOI":"10.3389\/fped.2016.00120"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1002\/ajmg.a.63023","article-title":"Increased intracranial pressure in a patient with Congenital Heart Defect and Ectodermal Dysplasia (CHDED): Extension of phenotype and review of literature","volume":"191","author":"Alghaith","year":"2023","journal-title":"Am. J. Med. Genet. Part A"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1048\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T09:28:31Z","timestamp":1788427711000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1048"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,30]]},"references-count":20,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["genes17091048"],"URL":"https:\/\/doi.org\/10.3390\/genes17091048","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,30]]}}}