120: When the Clock Breaks: BMAL1 Variants and a Neurodevelopmental Syndrome

Cuddapah VA et al., Proceedings of the National Academy of Sciences (PNAS) - An international series of 10 individuals with ultrarare heterozygous BMAL1 variants present a syndromic neurodevelopmental phenotype (developmental delay, autism, variable sleep issues, seizures, marfanoid features). Functional assays in human cells and Drosophila show both loss- and gain-of-function effects on BMAL1 activity, PER2 expression, circadian rhythms, and memory, supporting BMAL1 disruption as a cause of neurodevelopmental disease. Key terms: BMAL1, neurodevelopmental disorder, circadian rhythms, developmental delay, Drosophila. Study Highlights:Through gene-matching the authors identified 10 individuals carrying ultrarare BMAL1 variants, many de novo, sharing developmental delay and autism spectrum disorder. CRISPR-edited U2OS Per2-dLuc reporter lines showed 8/9 tested variants altered PER2 transcription and circadian parameters, indicating loss- or gain-of-function effects. Two conserved variants modeled in Drosophila produced variant-dependent changes in locomotor rhythms and impaired short- and long-term memory. Together the cellular and in vivo data support pathogenicity of BMAL1 variants in a neurodevelopmental syndrome. Conclusion:Ultrarare heterozygous BMAL1 variants can disrupt molecular clock function and contribute to a syndromic neurodevelopmental disorder; these results motivate further study of circadian-targeted assessment and interventions in affected individuals. Music:Enjoy the music based on this article at the end of the episode. Article title:Rare variants in BMAL1 are associated with a neurodevelopmental syndrome First author:Cuddapah VA Journal:Proceedings of the National Academy of Sciences (PNAS) DOI:10.1073/pnas.2427085122 Reference:Cuddapah VA, Chen D, Cho B, et al. Rare variants in BMAL1 are associated with a neurodevelopmental syndrome. Proc Natl Acad Sci U S A. 2025;122(31):e2427085122. doi:10.1073/pnas.2427085122 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/rare-bmal1-variants-link-the-circadian-clock-to-neurodevelopment QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-28. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantive auditing of sections describing BMAL1 clock mechanism, patient cohort and variants, cell-based PER2-dLuc assays, BMAL1 expression and CLOCK interaction, Drosophila cycle model and memory outcomes, and the clinical sleep phenotype discussion.- transcript topics: BMAL1 clock mechanism overview; GeneMatcher cohort (10 individuals) and ultrarare BMAL1 variants; CRISPR-edited U2OS Per2-dLuc cell assays; BMAL1 expression and CLOCK interaction; Drosophila cycle ortholog modeling; Memory assays in flies (short-term and long-term) QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- Ten individuals with ultrarare BMAL1 variants identified in the cohort.- Eight of nine tested BMA... Chapters (00:00:00) - Sleep disorders and the circadian clock(00:07:06) - BMAL1 variants disrupting the circadian clock(00:11:02) - BMA1 Syndrome in humans(00:16:07) - BMAO1 genetic variants and neurodevelopmental disorders(00:21:03) - Circadian clock gene variants in autism