Rare variants in <i>BMAL1</i> are associated with a neurodevelopmental syndrome.

Abstract

Through international gene-matching efforts, we identified 10 individuals with ultrarare heterozygous variants, including 5 de novo variants, in <i>BMAL1</i>, 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 <i>BMAL1</i> 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 <i>Per2</i>-promoter driven luciferase reporter and revealed both loss-of-function and gain-of-function changes in circadian rhythms. The tested <i>BMAL1</i> variants disrupted <i>PER2</i> mRNA cycling, but did not cause significant shifts in cellular localization or binding with CLOCK. Conserved variants were further tested in <i>Drosophila</i>, which confirmed variant-dependent effects on behavioral rhythms. Remarkably, flies expressing variant <i>cycle</i>, the ortholog of <i>BMAL1</i>, 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 <i>BMAL1</i> core clock gene contribute to a neurodevelopmental disorder.