Rare variants in are associated with a neurodevelopmental syndrome.

Through international gene-matching efforts, we identified 10 individuals with ultrarare heterozygous variants, including 5 de novo variants, in , a core component of the molecular clock. Instead of an isolated circadian phenotype seen with disease-causing variants in other molecular clock genes, all individuals carrying variants surprisingly share a clinical syndrome manifest as developmental delay and autism spectrum disorder, with variably penetrant sleep disturbances, seizures, and marfanoid habitus. Variants were functionally tested in cultured cells using a -promoter driven luciferase reporter and revealed both loss-of-function and gain-of-function changes in circadian rhythms. The tested variants disrupted mRNA cycling, but did not cause significant shifts in cellular localization or binding with CLOCK. Conserved variants were further tested in , which confirmed variant-dependent effects on behavioral rhythms. Remarkably, flies expressing variant , the ortholog of , also demonstrated deficits in short- and long-term memory, reminiscent of the highly prevalent developmental delay observed in our cohort. We suggest that ultrarare variants in the core clock gene contribute to a neurodevelopmental disorder.