Rare variants in BMAL1 are associated with a neurodevelopmental syndrome

• 成果类型: Article
• 署名作者: Cuddapah, Vishnu Anand; Chen, Dechun; Cho, Bumsik; Moore, Rebecca; Suri, Mohnish; Safraou, Hana; Tran-Mau-Them, Frederic; Wilson, Ashley; Odgis, Jacqueline; Rehman, Atteeq U.; Saunders, Carol; Ganesan, Shiva; Jobanputra, Vaidehi; Scherer, Stephen W.; Helbig, Ingo; Sehgal, Amita
• 署名单位: Baylor College of Medicine; Baylor College Medical Hospital; Baylor College of Medicine; Howard Hughes Medical Institute; University of Pennsylvania; University of Pennsylvania; Nottingham University Hospital NHS Trust; Universite Bourgogne Europe; CHU Dijon Bourgogne; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Bourgogne Europe; Icahn School of Medicine at Mount Sinai; University of Missouri System; University of Missouri Kansas City; Children's Mercy Hospital; University of Missouri System; University of Missouri Kansas City; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; NewYork-Presbyterian Hospital; Columbia University; University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; University of Toronto; University of Pennsylvania
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13112
• DOI: 10.1073/pnas.2427085122
• 发表日期: 2025-08-05
• 关键词: long-term-memory; sleep; Mutation; individuals; phenotype; insights; genes

摘要

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