The PPP2CA gene encodes the α isoform of the catalytic subunit C of protein phosphatase 2A (PP2A), an intracellular serine/threonine phosphatase. PPP2CA was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2019 (Reynhout et al., PMID: 30595372). The disorder is characterized by variable clinical features, including global developmental delay, mild to profound intellectual disability, hypotonia, autism spectrum disorder, seizures, and abnormalities on brain imaging, including enlarged ventricles, thin corpus callosum, and sometimes small brainstem.Some individuals may have microcephaly, macrocephaly, or nonspecific dysmorphic features.
Nine variants (four missense, three nonsense, one frameshift, and one in-frame duplication) that have been reported in nine probands in two publications (PMIDs: 30595372, 36531959) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. All reported variants are de novo. The mechanism of pathogenicity is reported to be loss of function, arising from multiple mechanisms, such as loss of enzymatic activity and disruption of PP2A holoenzyme assembly by impairing interactions with the regulatory and scaffolding subunits. Additionally, variants in the C-terminal region of the protein, which is involved in methylation-dependent regulation and B subunit recruitment, are proposed to have a dominant-negative effect (PMID: 40555839).
This gene-disease relationship is also supported by experimental evidence, including protein interaction and biochemical function. In the brain, PP2A phosphatases regulate cortical development, synaptic transmission, and hippocampus-dependent memory (PMID: 34241636). Pathogenic variants in other members of the protein phosphatase 2A gene family, PPP2R1A, PPP2R5D, and PPP2R5C, also cause neurodevelopmental disorders with overlapping phenotypes.
In summary, there is definitive evidence supporting the relationship between PPP2CA and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 7, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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