Individuals with reported and novel KDM5C variants present with seizures, a feature recapitulated in a Drosophila model.

Variants in the chromatin regulator KDM5C cause a rare neurodevelopmental disorder (KDM5C-NDD) characterized by intellectual disability, seizures, and a broad range of systemic features. To better understand this disorder, more detailed and standardized information is required regarding the association between these genetic variants and cognitive and behavioral traits. Utilizing data obtained by the RARE-X KDM5C Data Collection Program, we analyzed survey and genetic data from 31 newly reported individuals. In addition to the expected neurodevelopmental challenges, participants frequently reported growth abnormalities, vision and digestive issues, behavioral concerns, and seizures in nearly half of cases. Meta-analyses of this data, combined with information from previously published cases, reaffirmed that seizures are a frequent feature in both male and female individuals with KDM5C variants, with over a third of individuals having had at least one seizure. Based on the prevalence of seizures in the RARE-X and published datasets, we next sought to explore the mechanisms underlying this behavior using the model organism Drosophila to develop robust quantitative assays of seizure-like behavior by modulating the expression of its single Kdm5 gene. Loss of KDM5 specifically in neurons, but not glia, led to spontaneous and stimulus-induced seizures, underscoring a cell-intrinsic requirement for KDM5 in maintaining neuronal stability. Together, these human and fly studies highlight KDM5C as a critical regulator of nervous system function and demonstrate how patient-driven data collection and scalable model systems can be integrated. This work broadens our understanding of KDM5C-NDD and lays the foundation for future therapeutic discovery.