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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. Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. 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. 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.


Lisa Lenaerts, Sara Reynhout, Iris Verbinnen, Frédéric Laumonnier, Annick Toutain, Frédérique Bonnet-Brilhault, Yana Hoorne, Shelagh Joss, Anna K Chassevent, Constance Smith-Hicks, Bart Loeys, Pascal Joset, Katharina Steindl, Anita Rauch, Sarju G Mehta, Wendy K Chung, Koenraad Devriendt, Susan E Holder, Tamison Jewett, Lauren M Baldwin, William G Wilson, Shelley Towner, Siddharth Srivastava, Hannah F Johnson, Cornelia Daumer-Haas, Martina Baethmann, Anna Ruiz, Elisabeth Gabau, Vani Jain, Vinod Varghese, Ali Al-Beshri, Stephen Fulton, Oded Wechsberg, Naama Orenstein, Katrina Prescott, Anne-Marie Childs, Laurence Faivre, Sébastien Moutton, Jennifer A Sullivan, Vandana Shashi, Suzanne M Koudijs, Malou Heijligers, Emma Kivuva, Amy McTague, Alison Male, Yvette van Ierland, Barbara Plecko, Isabelle Maystadt, Rizwan Hamid, Vickie L Hannig, Gunnar Houge, Veerle Janssens. The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction. Genetics in medicine : official journal of the American College of Medical Genetics. 2021 Feb;23(2):352-362

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PMID: 33106617

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