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ResearchIn-Press PreviewCell biologyGeneticsVascular biology Open Access | 10.1172/JCI186287

CDKL1 variants affecting ciliary formation predispose to thoracic aortic aneurysm and dissection

Theresa Nauth,1 Melanie Philipp,2 Sina Renner,1 Martin D. Burkhalter,2 Helke Schüler,3 Ceren Saygi,4 Kristian Händler,5 Bente Siebels,6 Alice Busch,1 Thomas Mair,6 Verena Rickassel,1 Sophia Deden,1 Konstantin Hoffer,7 Jakob Olfe,8 Thomas S. Mir,8 Yskert von Kodolitsch,3 Evaldas Girdauskas,9 Meike Rybczynski,3 Malte Kriegs,7 Hannah Voß,6 Thomas Sauvigny,10 Malte Spielmann,5 Malik Alawi,4 Susanne Krasemann,11 Christian Kubisch,1 Till J. Demal,9 and Georg Rosenberger1

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Nauth, T. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Philipp, M. in: PubMed | Google Scholar |

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Renner, S. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Burkhalter, M. in: PubMed | Google Scholar |

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Schüler, H. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Saygi, C. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Händler, K. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Siebels, B. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Busch, A. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Mair, T. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Rickassel, V. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Deden, S. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Hoffer, K. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Olfe, J. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Mir, T. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by von Kodolitsch, Y. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Girdauskas, E. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Rybczynski, M. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Kriegs, M. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Voß, H. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Sauvigny, T. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Spielmann, M. in: PubMed | Google Scholar

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Alawi, M. in: PubMed | Google Scholar |

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Krasemann, S. in: PubMed | Google Scholar |

1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Experimental and Clinical Pharmacology and Pharmacogenomics, , Eberhard-Karls-University Tübingen, Tübingen, Germany

3Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany

4Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany

6Section Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7University Cancer Center Hamburg (UCCH) Kinomics Core Facility, Hubertus Wa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8Clinic for Children’s Heart Medicine and Adult Congenital Heart Disease, University Heart & Vascular Center Hamburg, Hamburg, Germany

9Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany

10Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

11Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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Published October 7, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI186287.
Copyright © 2025, Nauth et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 7, 2025 - Version history
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Abstract

Genetic factors are fundamental in the etiology of thoracic aortic aneurysm and dissection (TAAD), but the genetic cause is detected in only about 30% of cases. To define unreported TAAD-associated sequence variants, exome and gene panel sequencing was performed in 323 patients. We identified heterozygous CDKL1 variants [c.427T>C p.(Cys143Arg), c.617C>T p.(Ser206Leu), and c.404C>T p.(Thr135Met)] in 6 patients from 3 families with TAAD-spectrum disorders. CDKL1 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. Co-injection of human CDKL1wildtype, but not CDKL1Cys143Arg and CDKL1Ser206Leu RNA, rescued ISV malformations. All variants affected CDKL1 kinase function and profiling data, and altered protein-protein binding properties, particularily with ciliary transport molecules. Expression of CDKL1 variants in heterologeous cells interfered with cilia formation and length, CDKL1 localization, and p38-MAPK and Vegf signaling. Our data suggest a role of CDKL1 variants in the pathogenesis of TAAD-spectrum disorders. The association between primary cilia dysregulation and TAAD expands our knowledge of the underlying molecular pathophysiology.

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