️Episode 120: Rare BMAL1 Variants Link the Circadian Clock to Neurodevelopment

In this episode of PaperCast Base by Base, we explore how ultrarare heterozygous variants in BMAL1—a core circadian clock gene—are associated with a neurodevelopmental syndrome featuring developmental delay, autism spectrum disorder, and musculoskeletal findings.

Study Highlights:
The authors identified ten individuals carrying very rare BMAL1 variants, five of which were de novo, and documented overlapping clinical features including developmental delay and autism spectrum disorder with variably penetrant sleep disturbances and marfanoid traits. Functional assays in U2OS cells using a Per2 promoter–driven luciferase reporter showed that most variants disrupted BMAL1 activity via altered period, phase, or amplitude of molecular rhythms, with frameshift and splice-site changes trending toward loss of function while a PAS1 missense variant (Ile201Thr) enhanced rhythmic output. PER2 and NR1D1 mRNA cycling confirmed variant‑dependent effects on clock-controlled transcription without grossly altering BMAL1 localization or CLOCK binding. In Drosophila, orthologous variants in cycle (cyc) reproduced gain‑ and loss‑of‑function effects on behavioral rhythms and, notably, both classes impaired short‑ and long‑term memory, connecting core clock disruption to neurodevelopment‑relevant phenotypes.

Conclusion:
These findings implicate rare BMAL1 variants as contributors to a Mendelian neurodevelopmental disorder and suggest that targeting sleep and circadian pathways could be an avenue to mitigate cognitive and developmental impacts.

Reference:
Cuddapah VA, Chen D, Cho B, Moore R, Suri M, Safraou H, Tran‑Mau‑Them F, Wilson A, Odgis J, Rehman AU, Saunders C, Ganesan S, Jobanputra V, Scherer SW, Helbig I, Sehgal A. Rare variants in BMAL1 are associated with a neurodevelopmental syndrome. PNAS. 2025;122(31):e2427085122. https://doi.org/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:
If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

Keywords: BMAL1; circadian rhythms; neurodevelopmental disorder; autism spectrum disorder; Drosophila memory