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To define unreported TAAD-associated sequence variants, exome and gene panel sequencing was performed in 323 patients. We identified heterozygous\n                    <jats:italic>CDKL1<\/jats:italic>\n                    variants [c.427T&gt;C p.(Cys143Arg), c.617C&gt;T p.(Ser206Leu), and c.404C&gt;T p.(Thr135Met)] in 6 patients from 3 families with TAAD spectrum disorders.\n                    <jats:italic>CDKL1<\/jats:italic>\n                    encodes a protein kinase involved in ciliary biology. Amino acid substitutions were predicted to affect CDKL1 catalytic activity or protein binding properties. CDKL1 was expressed in vascular smooth muscle cells in normal and diseased human aortic wall tissue. Cdkl1 knockdown and transient knockout in zebrafish resulted in intersomitic vessel (ISV) malformations and aortic dilation. Coinjection of human\n                    <jats:italic>\n                      CDKL1\n                      <jats:sup>wild-type<\/jats:sup>\n                    <\/jats:italic>\n                    RNA, but not\n                    <jats:italic>\n                      CDKL1\n                      <jats:sup>Cys143Arg<\/jats:sup>\n                    <\/jats:italic>\n                    and\n                    <jats:italic>\n                      CDKL1\n                      <jats:sup>Ser206Leu<\/jats:sup>\n                    <\/jats:italic>\n                    RNA, rescued ISV malformations. All variants affected CDKL1 kinase function and profiling data, and altered protein-protein binding properties, particularly with ciliary transport molecules. Expression of CDKL1 variants in heterologous cells interfered with cilia formation and length, CDKL1 localization, and p38 MAPK and Vegf signaling. Our data suggest a role of\n                    <jats:italic>CDKL1<\/jats:italic>\n                    variants in the pathogenesis of TAAD spectrum disorders. The association between primary cilia dysregulation and TAAD expands our knowledge of the underlying molecular pathophysiology.\n                  <\/jats:p>","DOI":"10.1172\/jci186287","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T16:00:12Z","timestamp":1759852812000},"source":"Crossref","is-referenced-by-count":5,"title":["CDKL1 variants affecting ciliary formation predispose to thoracic aortic aneurysm and dissection"],"prefix":"10.1172","volume":"135","author":[{"given":"Theresa","family":"Nauth","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2714-965X","authenticated-orcid":true,"given":"Melanie","family":"Philipp","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Section of Pharmacogenomics, Eberhard-Karls-University T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sina","family":"Renner","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8646-3131","authenticated-orcid":true,"given":"Martin D.","family":"Burkhalter","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Section of Pharmacogenomics, Eberhard-Karls-University T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helke","family":"Sch\u00fcler","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ceren","family":"Saygi","sequence":"additional","affiliation":[{"name":"Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"H\u00e4ndler","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Universit\u00e4tsklinikum Schleswig-Holstein (UKSH), University of L\u00fcbeck and University of Kiel, L\u00fcbeck, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bente","family":"Siebels","sequence":"additional","affiliation":[{"name":"Section Mass Spectrometry and Proteomics, Center for Diagnostics;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Busch","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Mair","sequence":"additional","affiliation":[{"name":"Section Mass Spectrometry and Proteomics, Center for Diagnostics;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Rickassel","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Deden","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin","family":"Hoffer","sequence":"additional","affiliation":[{"name":"University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wald Tumorzentrum\u2013UCCH; 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