Purpose: Neurodevelopmental disorders (NDD) caused by protein
phosphatase 2A (PP2A) dysfunction have mainly been associated
with de novo variants in PPP2R5D and PPP2CA, and more rarely in
PPP2R1A. Here, we aimed to better understand the latter by
characterizing 30 individuals with de novo and often recurrent
variants in this PP2A scaffolding Aα subunit.
Methods: Most cases were identified through routine clinical
diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits.
Results: We describe 30 individuals with 16 different variants in
PPP2R1A, 21 of whom had variants not previously reported. The severity
of developmental delay ranged from mild learning problems to severe
intellectual disability (ID) with or without epilepsy. Common features
were language delay, hypotonia, and hypermobile joints. Macrocephaly
was only seen in individuals without B55α subunit-binding deficit, and
these patients had less severe ID and no seizures. Biochemically more
disruptive variants with impaired B55α but increased striatin binding
were associated with profound ID, epilepsy, corpus callosum hypoplasia,
and sometimes microcephaly.
Conclusion: We significantly expand the phenotypic spectrum of
PPP2R1A-related NDD, revealing a broader clinical presentation of the
patients and that the functional consequences of the variants are more
diverse than previously reported