Abstract Variants that disrupt the function of 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 the cases. Meta-analyses of this data and previously published cases reaffirmed that seizures are a frequent feature in both hemizygous males and heterozygous females with KDM5C variants, with over a third of individuals reporting at least one seizure. Based on the prevalence of seizures in the RARE-X and published datasets, we sought to develop robust quantitative assays of KDM5-associated seizure behavior using the model organism Drosophila. Reducing the expression of its single Kdm5 gene 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, demonstrating how patient-driven data collection and scalable model systems can be effectively integrated. This work expands our understanding of KDM5C-NDD and lays the groundwork for future therapeutic discoveries.
Terry et al. (Sat,) studied this question.