Advanced Optical Microscopy: Unveiling Functional Insights Regarding a Novel PPP2R1A Variant and Its Unreported Phenotype

The number of genes implicated in neurodevelopmental conditions is rapidly growing. Recently, variants in <i>PPP2R1A</i> have been associated with syndromic intellectual disability and a consistent, but still expanding, phenotype. The <i>PPP2R1A</i> gene encodes a protein subunit of the serine/threonine protein phosphatase 2A enzyme, which plays a critical role in cellular function. We report an individual showing pontocerebellar hypoplasia (PCH), microcephaly, optic and peripheral nerve abnormalities, and an absence of typical features like epilepsy and an abnormal corpus callosum. He bears an unreported variant in an atypical region of <i>PPP2R1A</i>. In silico studies, functional analysis using immunofluorescence, and super-resolution microscopy techniques were performed to investigate the pathogenicity of the variant. This analysis involved a comparative analysis of the patient's fibroblasts with both healthy control cells and cells from an individual with the previously described phenotype. The results showed reduced expression of <i>PPP2R1A</i> and the presence of aberrant protein aggregates in the patient's fibroblasts, supporting the pathogenicity of the variant. These findings suggest a potential association between <i>PPP2R1A</i> variants and PCH, expanding the clinical spectrum of <i>PPP2R1A</i>-related neurodevelopmental disorder. Further studies and descriptions of additional patients are needed to fully understand the genotype-phenotype correlation and the underlying mechanisms of this novel phenotype.