Transcriptomic signatures in brain and blood related to cognitive and psychiatric phenotypes of Prader-Willi syndrome

This study defined gene expression changes across different cell types in prefrontal cortex (PFC) of donors with Prader-Willi syndrome (PWS) compared to controls and examined relationships between these changes in blood and PWS symptoms. 8,338 long non-coding RNAs and 17,079 protein-coding genes were examined using single-nucleus RNA-sequencing (snRNA-seq) in the PFC of 8 donors with PWS (4 deletion, 4 non-deletion), and 4 age- and sex-matched neurotypical controls. snRNA-seq analyses showed an increased proportion of interneurons in both PWS groups compared to controls. Fifty-four genes and related pathways were consistently dysregulated across all cell types in the PFC of the PWS group compared to controls, with RPS18 being the only protein-coding gene upregulated in PWS PFC across all comparisons. Increase in RPS18 mRNA levels in peripheral blood mononuclear cells (PBMCs) of another cohort (16 deletion, 20 non-deletion, ages 1-45 years) assessed using droplet digital PCR was found to be associated with intellectual functioning and challenging behaviors, but not autistic traits in children with PWS due to non-deletion (< 13 years old; N = 19). If confirmed in future studies, these findings may lead to development of prognostic biomarkers and therapeutics targeting consistently dysregulated genes and related pathways between brain and periphery.