The clinical, neuroimaging, and molecular characteristics of PPP2R5D related neurodevelopmental disorders: an expanded series with functional characterization and genotype-phenotype correlation

Genetics variants in the PPP2R5D gene have been identified to cause a neurodevelopmental disorder characterized by intellectual disabilities, autism spectrum disorder and epilepsy, among others features. Our study, describing 76 individuals, expands the known clinical and molecular spectrum of PPP2R5D related disorders. This allowed us to identify a correlation between groups of variants and their clinical features. Using biochemical assays, we found that not all variants affect the protein in the same way, leading us to conclude that some variants may cause more severe disease than others. Our data will be useful in both clinical evaluations and treatment of affected individuals. (Nora M Oyama, Pieter Vaneynde, Sara Reynhout, Emily C Pao, Andrew Timms, Xiao Fan, Kimberly Foss, Rita Derua, Veerle Janssens, Wendy K Chung and Ghayda M Mirzaa, )

Structural representation of the PPP2R5D variants reported in this study within the PP2A holoenzyme and gene diagram of PPP2R5D. (A) Side view of the PP2A holoenzyme, brown denotes the catalytic C subunit, blue the scaffolding A subunit, and grey the B56δ subunit. (B) 90°-degree rotation of (A) with red denoting pathogenic variants, orange variants of unknown significance, green the SLIM-binding domain of B56δ, and blue the catalytic pocket of the C subunit. The structure was generated based on PP2A-B56γ1 crystallographic data (PDB 2IAE) and visualized in Molsoft MolBrowser 3.9-2d software (ICM-Broser-Pro).

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