Tackling ciliary specialization to understand phenotypic variability in human primary ciliopathies

Primary cilia are crucial cellular organelles with vital roles in signal transduction and cellular function. Disruptions in primary ciliary structure or function underlie a group of genetic disorders known as primary ciliopathies. These disorders present as a diverse range of clinical features with prominent phenotypic variability, often complicating their diagnosis and the basic understanding of their underlying molecular mechanisms. To grasp this complexity, the ciliopathy field is moving from a static view of primary cilia towards a more comprehensive understanding of their dynamic and specialized cell-type-specific roles. By building on the large amount of knowledge gathered over the past decades and by employing recently developed tools, including multi-omics and human cell-based in vitro models, we can now interrogate ciliary specialization to understand the role of cilia in each tissue and the consequences of ciliary gene dysfunction on human health. This Perspective explores the current challenges and opportunities associated with these modern tools and databases, highlighting important action points to advance our understanding of this fascinating organelle and its role in human health and disease.