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Publication Q&A: Clinical, Neuroimaging and Molecular Characteristics of PPP2R5D-related Neurodevelopmental Disorders: An Expanded Series with Functional Characterisation and Genotype–Phenotype Analysis

October 2022 – Dr. Ghayda Mirzaa, principal investigator in Seattle Children’s Center for Integrative Brain Research and assistant professor of pediatrics and genetics at the University of Washington School of Medicine, and colleagues share their work identifying new genetic variants and an inherited variant in PPP2R5D, which causes neurodevelopmental challenges in children. The research could aid better treatment and clinical management. 

Nora Oyama*, Pieter Vaneynde, Sara Reynhout, Emily Pao*, Andrew Timms*, Xiao Fan, Kimberly Foss, Rita Derua, Veerle Janssens, Wendy Chung, Ghayda Mirzaa*

Published Oct. 10, 2022

Read this article in the Journal of Medical Genetics.

What are the significant findings in this paper?

Our study reports the largest series of children (a total of 76) with genetic changes in PPP2R5D, an important phosphatase that plays key roles in neurodevelopment. We identified several new genetic variants and the first instance of an inherited variant from an affected parent. Functional analysis allowed us to further understand the possible mechanisms by which these genetic variants act, as well as identify subgroups with clinical differences to better understand relationships between genotypes and phenotypes. Common clinical features include intellectual disability (80.6%), hypotonia (75.0%), a large head size or macrocephaly (66.7%), seizures (45.8%) and autism spectrum disorder (26.4%).

What does this research tell us that we didn’t know before?

Our significantly expanded series of individuals with PPP2R5D variants enabled us to better characterize the association of this gene with neurodevelopmental disorders, neurobehavioral issues and other notable clinical features, as well as further our understanding of the molecular function and biochemical properties of causal PPP2R5D variants. We were also able to examine in detail the effects these genetic variants have on neurodevelopment.

What are the broad implications of this research?

The clinical, molecular, and functional data from this study have important consequences for clinical evaluations and aid in the future treatment for affected individuals. By better understanding the clinical and molecular spectrum of this disorder, we are better able to start neurodevelopmental therapies earlier, as well as other aspects of treatments.

What are the next steps and long-term goals for this research?

The data generated by this study will be used for natural history studies that will be used for clinical trial readiness. Efforts are currently underway to study therapeutic endpoints and identify treatment strategies for clinical trials in the near future.

Any other specific information should we know about this paper?

This was a highly collaborative project between Seattle Children’s, Simons Searchlight (one of the largest international research programs studying rare genetic neurodevelopmental disorders) and the PPP2R5D family foundation, Jordan’s Guardian Angels. Through this collaboration, data collected by Simons Searchlight from families was analyzed by our research team to better understand this disorder. Scientific collaborations, as exemplified by this study, are instrumental to advance rare disease research.

Learn more about Dr. Mirzaa’s research.

*Seattle Children’s contributing authors

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