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

Area of Science:

• Cardiovascular Genetics
• Molecular Biology
• Cilia Biology

Background:

• Genetic factors are key in thoracic aortic aneurysm and dissection (TAAD) etiology, yet the cause remains unknown in most patients.
• Identifying novel genetic variants is crucial for understanding TAAD pathogenesis.
• CDKL1's role in TAAD was previously unexplored.

Purpose of the Study:

• To identify unreported sequence variants associated with TAAD.
• To investigate the functional impact of identified CDKL1 variants.
• To explore the role of CDKL1 in aortic disease and primary cilia function.

Main Methods:

• Exome and gene panel sequencing in 323 TAAD patients.
• Functional studies in zebrafish (knockdown/knockout and RNA rescue).
• In vitro studies assessing variant effects on protein function, cilia, and signaling pathways.

Main Results:

• Heterozygous CDKL1 variants were identified in 6 patients from 3 families with TAAD spectrum disorders.
• CDKL1 variants affected kinase activity, protein binding, cilia formation, and signaling pathways (p38 MAPK, Vegf).
• Zebrafish models with Cdkl1 knockdown exhibited aortic dilation and ISV malformations, which were rescued by wild-type CDKL1 RNA.

Conclusions:

• CDKL1 variants are implicated in the pathogenesis of TAAD spectrum disorders.
• Dysregulation of primary cilia due to CDKL1 variants contributes to TAAD.
• This study expands the understanding of TAAD pathophysiology by linking it to ciliary dysfunction.