Sex-specific genotype-phenotype landscape and prevalence of <i>CASK</i> -related disorder

<jats:p> Disruptions to synaptic proteins cause a diverse group of rare monogenic neurodevelopmental disorders, yet their genetic architecture, genotype-phenotype relationships, and the population prevalence often remain poorly defined. Pathogenic variants in the X-linked gene <jats:italic>CASK</jats:italic> cause a spectrum of neurologic symptoms known collectively as <jats:italic>CASK</jats:italic> -related disorder. <jats:italic>CASK</jats:italic> encodes calcium/calmodulin-dependent serine protein kinase, a multi-domain scaffolding protein that is enriched in the nervous system and important for multiple biological processes. Cardinal clinical symptoms include global developmental delay, intellectual disability, microcephaly, pontine and cerebellar hypoplasia, epilepsy, and motor dysfunction. However, the genetic architecture, clinical spectrum, and prevalence of this disorder remain unclear. Here, we systematically define the sex-specific genotypic and phenotypic landscape of <jats:italic>CASK</jats:italic> -related disorder through quantitative analysis of 302 individuals with pathogenic <jats:italic>CASK</jats:italic> variants reported in the literature or rare disease databases and estimate the disease prevalence using large genetic cohort studies of individuals with neurodevelopmental disorders. We show that affected female heterozygous and male hemizygous individuals are present at an approximately 2:1 ratio but have distinct genetic architectures. The former predominantly harbor de novo loss-of-function variants, whereas the latter frequently carry maternally inherited missense variants. These contrasting genetic architectures underlie the observed differences in clinical presentation. While global developmental delay and motor dysfunction are nearly universal, female heterozygous individuals are more likely to have microcephaly and pontine and cerebellar hypoplasia, whereas male hemizygous individuals are more likely to develop epilepsy that is both earlier in onset, more severe, and independent of variant type. Within each sex, loss-of-function variants often confer more severe phenotypes than missense or splicing variants. We further estimate the prevalence of <jats:italic>CASK</jats:italic> -related disorder to be 0.57-2.09 per 100,000 children in the general population, providing the first population-based estimate of disease burden. Together, our results establish the sex-specific genetic architecture, genotype-phenotype relationships, and population prevalence of <jats:italic>CASK</jats:italic> -related disorder. These findings reveal how variant type and X-linked inheritance jointly shape disease expression and provide a foundation for improving diagnosis, genetic counseling, natural history studies, therapeutic development, and health policy planning for CASK-related disorder, with broader implications for other X-linked neurodevelopmental disorders. </jats:p>