Background Variants in PPP2R5D, affecting the regulatory B56δ subunit of protein phosphatase 2A (PP2A), have been identified in individuals with neurodevelopmental abnormalities. However, the molecular and clinical spectra remain incompletely understood.
Methods Individuals with PPP2R5D variants were enrolled through Simons Variation in Individuals Project/Simons Searchlight. Data were collected from medical history interviews, medical record review, online validated instruments and neuroimaging review. Genetic variants were biochemically characterised.
Results We studied 76 individuals with PPP2R5D variants, including 68 with pathogenic de novo variants, four with a variant of uncertain significance (VUS) and four siblings with a novel dominantly inherited pathogenic variant. Among 13 pathogenic variants, eight were novel and two (p.Glu198Lys and p.Glu200Lys) were highly recurrent. Functional analysis revealed impaired PP2A A/C-subunit binding, decreased short linear interaction motif-dependent substrate binding or both—with the most severe phenotypes associated with variants that completely retained one of these binding characteristics and lost the other—further supporting a dominant-negative disease mechanism. p.Glu198Lys showed the highest C-binding defect and a more severe clinical phenotype. The inherited p.Glu197Gly variant had a mild substrate binding defect, and three of four VUS had no biochemical impact. Common clinical phenotypes were language, intellectual or learning disabilities (80.6%), hypotonia (75.0%), macrocephaly (66.7%), seizures (45.8%) and autism spectrum disorder (26.4%). The mean composite Vineland score was 59.8, and most participants were in the ‘moderate to low’ and ‘low’ adaptive levels in all domains.
Conclusion Our study delineates the most common features of PPP2R5D-related neurodevelopmental disorders, expands the clinical and molecular spectrum and identifies genotype–phenotype correlations.
- Genetic Research
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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VJ, WC and GMM are joint senior authors.
NO and PV are joint first authors.
NO and PV contributed equally.
VJ, WC and GMM contributed equally.
Contributors VJ, WC and GMM conceived and designed the study, analysed the data and drafted the manuscript. NO and PV acquired and analysed the data and drafted the manuscript and figures. SR, EMP, AT, XF, KF and RD contributed to data acquisition, data analysis as well as editing the manuscript. VJ, WC, and GMM accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Funding We thank the families and Jordan’s Guardian Angels (JGA, https://jordansguardianangels.org/) for their contribution and support of this study. Research reported in this publication was supported by JGA (to GMM, WC and VJ), the Sunderland Foundation and the Brotman Baty Institute (to GMM), the Marguerite-Marie Delacroix Foundation (to PV) and the Research Foundation-Flanders (to SR). We are grateful to all the Simons Searchlight families, as well as the Simons VIP (Simons Searchlight) Consortium. We appreciate obtaining access to phenotypical and genetic data on SFARI Base. Researchers who obtained approval can obtain the Simons Searchlight population dataset described in this study by applying online (https://base.sfari.org)
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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