A multi-model approach defines function altering MECP2 missense variants identified in individuals with autism spectrum disorder
Pathogenic variants in MECP2 commonly lead to Rett syndrome, where MECP2s function as a DNA cytosine methylation reader is believed critical. MECP2 variants are also catalogued in individuals with autism spectrum disorder (ASD), including nine missense variants which had no known clinical significance at the start of this study. To assess these nine variants as risk alleles for ASD, we developed MECP2 variant functional assays using budding yeast and Drosophila. We calibrated these assays with known pathogenic and benign variants. Our data predict that four ASD variants are loss of function and five are functional. Protein destabilization offers insight into the altered function of some of these variants. Notably, yeast and Drosophila lack DNA methylation, yet all Rett pathogenic and ASD variants located in the methyl DNA binding domain that we analyzed proved to be loss of function, suggesting a clinically-relevant role for non-methyl DNA-binding by MECP2.