Primary cilia as a molecular convergence hub linking neurodevelopment and autism spectrum disorder

Abstract

The primary cilium, a highly conserved microtubule-based organelle, orchestrates a broad repertoire of signal transduction cascades required for embryonic development, tissue homeostasis and cellular communication. Disruption of ciliary structure or function results in a heterogeneous group of multisystem disorders known as ciliopathies. Emerging genomic and transcriptomic evidence indicates that perturbation of ciliary architecture or signaling may also contribute to neurodevelopmental conditions and specifically to autism spectrum disorder (ASD). Genes linked to ASD show a wide range of genetic and phenotypic characteristics: spanning from syndromic neurodevelopmental disorders with overlapping ciliopathy features to idiopathic ASD. Yet the mechanistic contribution of ASD risk genes to ciliary biology remains insufficiently characterized. This study aims to explore the molecular convergence between ciliopathies and ASD by systematically interrogating ciliary gene datasets (CiliaCarta and SysCilia GSv2) in cross-comparison to ASD-associated gene repositories (SFARI Gene). This integrative analysis identifies 105 high-confidence shared genes, which segregate into four mechanistic modules: (i) structural determinants of cilium assembly and maintenance, (ii) components of cilium-dependent signaling pathways, (iii) regulators of cilium-associated gene expression and (iv) cilium associated pathways. We propose that ciliary dysfunction constitutes a convergent mechanism, perturbing neurodevelopmental signaling, neuronal polarity and synaptic maturation in a subset of ASD cases. Clarifying the role of the genes shared between ciliogenesis and neurodevelopmental signaling will refine genotype-to-phenotype correlations, expand the spectrum of cilia-associated neurodevelopmental disorders and potentially uncover therapeutically actionable hubs within cilium-dependent signaling circuitry.