Clinical and molecular characteristics of a novel rare de novo variant in PPP2CA in a patient with a developmental disorder, autism, and epilepsy

Iris Verbinnen; Sara S Procknow; Lisa Lenaerts; Sara Reynhout; Aujan Mehregan; Chris Ulens; Veerle Janssens; Katherine A King

doi:10.3389/fcell.2022.1059938

Clinical and molecular characteristics of a novel rare de novo variant in PPP2CA in a patient with a developmental disorder, autism, and epilepsy

Front Cell Dev Biol. 2022 Nov 30:10:1059938. doi: 10.3389/fcell.2022.1059938. eCollection 2022.

Authors

Iris Verbinnen^{1

2}, Sara S Procknow³, Lisa Lenaerts¹, Sara Reynhout^{1

2}, Aujan Mehregan⁴, Chris Ulens⁴, Veerle Janssens^{1

2}, Katherine A King³

Affiliations

¹ Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Leuven, Belgium.
² KU Leuven Brain Institute (LBI), Leuven, Belgium.
³ Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States.
⁴ Laboratory of Structural Neurobiology, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Leuven, Belgium.

Abstract

PP2A-related (neuro) developmental disorders are a family of genetic diseases caused by a heterozygous alteration in one of several genes encoding a subunit of type 2A protein phosphatases. Reported affected genes, so far, are PPP2R5D, encoding the PP2A regulatory B56δ subunit; PPP2R1A, encoding the scaffolding Aα subunit; and PPP2CA, encoding the catalytic Cα subunit-in that order of frequency. Patients with a pathogenic de novo mutation in one of these genes, in part, present with overlapping features, such as generalized hypotonia, intellectual and developmental delay, facial dysmorphologies, seizures, and autistic features, and, in part, with opposite features, e.g., smaller versus larger head sizes or normal versus absent corpus callosum. Molecular variant characterization has been consistent so far with loss-of-function or dominant-negative disease mechanisms for all three affected genes. Here, we present a case report of another PPP2CA-affected individual with a novel de novo missense variant, resulting in a one-amino acid substitution in the Cα subunit: p.Cys196Arg. Biochemical characterization of the variant revealed its pathogenicity, as it appeared severely catalytically impaired, showed mildly affected A subunit binding, and moderately decreased binding to B/B55, B"/PR72, and all B56 subunits, except B56γ1. Carboxy-terminal methylation appeared unaffected, as was binding to B"'/STRN3-all being consistent with a partial loss of function. Clinically, the girl presented with mild-to-moderate developmental delay, a full-scale IQ of 83, mild dysmorphic facial features, tonic-clonic seizures, and autistic behaviors. Brain MRI appeared normal. We conclude that this individual falls within the milder end of the clinical and molecular spectrum of previously reported PPP2CA cases.

Keywords: PP2A-related neurodevelopmental disorders; PPP2CA; autism (ASD); case report; de novo mutation; developmental delay; epilepsy.