Rare variants inare associated with a neurodevelopmental syndrome.

Researchers studied 10 people with rare changes in a gene that controls our body's internal clock. Instead of just sleep problems, all participants had developmental delays and autism, plus sometimes seizures and unusual physical features. Tests showed these gene changes affected both sleep patterns and brain development. This suggests a new type of condition where clock gene problems cause autism and developmental delays, not just sleep issues.

This study identified 10 individuals with rare genetic variants in a core molecular clock gene, revealing an unexpected neurodevelopmental syndrome rather than isolated sleep problems. All participants showed developmental delay and autism spectrum disorder, with some experiencing sleep disturbances, seizures, and physical features resembling Marfan syndrome. Functional testing demonstrated both loss-of-function and gain-of-function effects on circadian rhythms, disrupting normal gene cycling patterns. Fruit fly studies confirmed behavioral rhythm disruptions and revealed memory deficits similar to the developmental delays observed in humans.

This research suggests that variants in this core clock gene contribute to a previously unrecognized neurodevelopmental disorder combining autism, developmental delays, and variable additional features.

This research identifies a new neurodevelopmental syndrome combining autism and developmental delays caused by clock gene variants. Clinicians should consider genetic testing for clock genes in autism cases with sleep disturbances or marfanoid features. Findings suggest circadian interventions might benefit this population.

Very small sample size (n=10) limits generalizability. Abstract lacks details on severity measures, diagnostic criteria, or long-term outcomes. No comparison group provided. Functional studies limited to cell culture and fruit fly models.

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 carryingvariants 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 testedvariants disruptedmRNA 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 thecore clock gene contribute to a neurodevelopmental disorder.