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:
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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/

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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 BMAL1 variants disrupted BMAL1 function in cell-based assays.
- BMAL1 Ile201Thr variant showed gain-of-function, increasing signal magnitude and advancing rhythm.
- Drosophila ortholog cycle variants exhibited variant-dependent effects on behavioral rhythms.
- Memory impairment observed in flies expressing variant cycle (short-term and long-term).
- Clinical phenotype includes developmental delay and autism; seizures present in a subset; marfanoid habitus observed in subset.

QC result: Pass.