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1. Novel heterozygous CDKL1 variants (p.Cys143Arg, p.Ser206Leu, p.Thr135Met) were identified in six patients across three families with thoracic aortic aneurysm and dissection (TAAD)-spectrum disorders.
2. CDKL1 encodes a cilia-associated protein kinase whose variants impair kinase activity, protein-protein interactions, and ciliary formation.
3. Functional assays in zebrafish models and heterologous cells demonstrated vascular malformations, defective cilia morphology, and disrupted signaling pathways (p38-MAPK, Vegf) caused by CDKL1 variants.
4. These findings establish primary cilia dysregulation as a novel mechanistic pathway underpinning TAAD pathogenesis.
