Koolen-de Vries Syndrome causal gene KANSL1 is required for motile ciliogenesis

Koolen-de Vries Syndrome (KdVS), characterized by hypersociability, intellectual disability, and seizures, is caused by pathogenic variants in the gene KANSL1, which encodes a chromatin regulator in the NSL complex that also directly functions in mitotic spindle microtubule stability. Here we explored whether KANSL1 functions at the cilium, a microtubule-rich organelle critical for brain development, neuronal excitability, and sensory integration. Leveraging the Xenopus model, we found that Kansl1 is highly expressed in developing ciliated tissues and localizes within motile cilia. Moreover, Kansl1 depletion caused ciliogenesis defects that could be partially rescued by human KANSL1. Based on these findings, we explored the prevalence of cilia-related clinical features including structural heart defects, hypogonadism, and structural respiratory defects among 99 individuals with KdVS, ages 1 month to 37 years old. To directly test if KdVS causes ciliary dysfunction in humans, we measured the well-established ciliary functional biomarker, nasal nitric oxide, in 11 affected individuals and observed a significant decrease when compared to unaffected family members. Together, this work establishes a ciliary contribution of KANSL1 mutations to KdVS. This work adds to a growing literature highlighting the relevance of the cilium to neurodevelopmental disorders, particularly to those impacting sociability. Going forward, KANSL1 provides a unique opportunity to study a monogenic mechanism of hypersociability that may be useful in elaborating the molecular underpinnings of social behavior.