MBD5 deletion disrupts circadian gene expression and is associated with sleep disturbance in the 2q23.1 deletion syndrome. S. H. Elsea1,2, S. V. Mullegama1,2, Z. Shah2, R. Tahir2, L. Pugliesi2 1) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; 2) Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.

   2q23.1 deletion syndrome is a complex neurodevelopmental syndrome that includes intellectual disability, epilepsy, speech impairment, and autism spectrum disorder (ASD) and is caused by haploinsufficiency of MBD5. Sleep disturbance, while previously reported, has not been assessed in this population. Since phenotypically overlapping disorders like Smith-Magenis syndrome (SMS) and ASD have sleep phenotypes that impact daily living, we sought to clinically and molecularly characterize the circadian deficits in the 2q23.1 deletion syndrome. Caregiver surveys were used to gather information on sleep and activity habits of 20 children aged 9 mon to 11 y with 2q23.1 deletions. Caregivers reported many sleep concerns for their child, including difficulty falling asleep (46%), multiple nighttime wakings and early morning waking (74%), and use of medications to improve sleep (44%), features commonly observed in both autism spectrum disorder and SMS. Data from the Epworth Sleepiness Scale revealed 44% of school-age children with excessive daytime sleepiness, and sleep problems were reported to affect daily functioning of the child and the caregiver, thus impacting the overall well-being of the family. We previously showed that RAI1 directly modulates the transcription of CLOCK and that multiple circadian genes are dysregulated in SMS cell lines, so we used gene expression and ChIP-chip data to molecularly characterize the impact of MBD5 deletion on sleep/circadian rhythm pathways. Data show that RAI1, NR1D2, and PER3 were dysregulated in 2q23.1 deletion patient cell lines, similar to findings in SMS. Pathway analyses from gene expression microarrays of knockdown of MBD5 in SH-SY5Y cell lines confirmed patient cell line data, revealing dysregulation of circadian rhythm genes, including ATF2, ATF4, CLOCK, and PER3. ChIP-chip studies also suggest that MBD5 directly regulates the transcription of NR1D2. These data support MBD5 as a regulator of circadian rhythm gene expression, providing a molecular basis for the sleep phenotype present in 2q23.1 deletion syndrome. Overall, delineation of a sleep phenotype in 2q23.1 deletion syndrome and molecular data to support the phenotypic findings places this MBD5-associated disorder into a category of neurodevelopmental syndromes where sleep behaviors significantly impact daily function and identify pathways for targeted therapeutic intervention that may be common to several neurodevelopmental syndromes.

You may contact the first author (during and after the meeting) at