In-depth behavioral characterization of a rat model of Schaaf-Yang syndrome.

Abstract

Schaaf-Yang syndrome (SYS, OMIM #615547) is a rare neurodevelopmental disorder caused by truncating variants in the maternally imprinted MAGEL2 gene. It is characterized by intellectual disability, autism spectrum disorder, joint contractures, and feeding difficulties. Although MAGEL2 is deleted in most cases of Prader-Willi syndrome (PWS, OMIM #176270), SYS presents with more severe symptoms, suggesting pathogenic effects of truncated MAGEL2 beyond a mere loss of function. This study expands the behavioral characterization of a novel rat model ("Magel2rats") which carries a truncating mutation on the paternal allele of Magel2, offering greater construct validity for SYS than previous animal models with Magel2 deletion. While an initial study provided first insights, key domains within the behavioral phenotype of the model remained unexplored. Our comprehensive behavioral analysis, including home-cage monitoring, ultrasonic vocalization analysis, and precise gait assessment, identified several phenotypic alterations potentially relevant to the study of SYS. Magel2rats exhibited abnormal feeding behavior, changes in early social communication, alterations in gait, aberrant behavior in the elevated plus maze, and delayed decision-making. Additionally, we confirmed that Magel2rats show phenotypes of abnormal social interaction. These results may reflect core symptoms seen in SYS, underscoring the value of this model for preclinical research on pathophysiology and therapeutics.