PPP2R1A was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2015 (PMIDs: 25533962, 26168268). Individuals with PPP2R1A pathogenic variants present with developmental delay, intellectual disability, hypotonia, and language delay (PMIDs: 26168268, 33106617). Other common features include hypermobile joints, behavioral problems, epilepsy, and macrocephaly (PMIDs: 26168268, 33106617). Over 30 individuals with neurodevelopmental disorders and a de novo PPP2R1A missense variant have been reported in the literature (PMIDs: 26168268, 31531803, 31687265, 33106617). Only 10 probands are included in this curation because the maximum score for genetic evidence has been reached.
PPP2R1A encodes the scaffolding Aα subunit of protein phosphatase type 2A (PP2A). The Aα subunit acts as a scaffolding molecule, coordinating the assembly of the catalytic C subunit and a variable regulatory B subunit to produce functionally diverse PP2A heterotrimers (PMID: 9989501). PPP2R1A variants cluster in the HEAT repeat and intrarepeat region of the protein (PMID: 33106617). The reported de novo recurrent and clustered missense variants that reduce catalytic C subunit binding, as well as variants that decrease PP2A activity but not catalytic subunit binding, suggest that PPP2R1A variants cause PP2A dysfunctions via both dominant-negative and haploinsufficiency mechanisms (PMIDs: 26168268, 33106617). The gene-disease relationship is also supported by experimental evidence, including protein interaction and biochemical function (PMIDs: 26168268, 33106617).
In summary, there is definitive evidence to support the relationship between PPP2R1A and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 16, 2022 (SOP Version 9).
PPP2R1A was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2015 (PMIDs: 25533962, 26168268). Individuals with PPP2R1A pathogenic variants present with developmental delay, intellectual disability, hypotonia, and language delay (PMIDs: 26168268, 33106617). Other common features include hypermobile joints, behavioral problems, epilepsy, and macrocephaly (PMIDs: 26168268, 33106617). Over 30 individuals with neurodevelopmental disorders and a de novo PPP2R1A missense variant have been reported in the literature (PMIDs: 26168268, 31531803, 31687265, 33106617). Only 10 probands are included in this curation because the maximum score for genetic evidence (12 points) has been reached.
PPP2R1A encodes the scaffolding Aα subunit of protein phosphatase type 2A (PP2A). The Aα subunit acts as a scaffolding molecule, coordinating the assembly of the catalytic C subunit and a variable regulatory B subunit to produce functionally diverse PP2A heterotrimers (PMID: 9989501). PPP2R1A variants cluster in the HEAT repeat and intrarepeat region of the protein (PMID: 33106617). The reported de novo recurrent and clustered missense variants that reduce catalytic C subunit binding, as well as variants that decrease PP2A activity but not catalytic subunit binding, suggest that PPP2R1A variants cause PP2A dysfunctions via both dominant-negative and haploinsufficiency mechanisms (PMIDs: 26168268, 33106617). The gene-disease relationship is also supported by experimental evidence, including protein interaction and biochemical function (PMIDs: 26168268, 33106617).
In summary, there is definitive evidence supporting the relationship between PPP2R1A 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 November 16, 2022 (SOP Version 9).
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