Exploring the molecular pathways linking sleep phenotypes and POGZ-associated neurodevelopmental disorder

Pogo transposable element-derived protein with ZNF domain (POGZ) gene encodes a chromatin regulator and rare variants in this gene have been associated with a broad spectrum of neurodevelopmental disorders, such as White-Sutton syndrome. Patient clinical manifestations frequently include developmental delay, autism spectrum disorder and obesity. Sleep disturbances are also commonly observed in these patients, yet the biological pathways linking sleep traits to the POGZ-associated syndrome remain unclear. We screened for sleep implications among individuals with causative POGZ variants previously described. Sleep disturbances were observed in 52% of patients, and obesity was not observed to be a risk factor for sleep problems. Next, we identified genes associated with sleep-related traits among the POGZ regulatory targets, aiming to uncover molecular pathways that, when disrupted by POGZ loss of function, contribute to the etiology of sleep phenotypes in these patients. The overlap between POGZ targets and sleep-related genes was used in pathway enrichment analysis. Relevant pathways among these overlapping genes are involved in regulation of circadian rhythm, tau protein binding, and ATPase activator activity. This study represents a starting point for novel functional investigations into shared molecular mechanisms between sleep disturbances and rare developmental syndromes related to POGZ and its regulatory targets.