TY - JOUR
T1 - The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction
AU - Lenaerts, Lisa
AU - Reynhout, Sara
AU - Verbinnen, Iris
AU - Laumonnier, Frédéric
AU - Toutain, Annick
AU - Bonnet-Brilhault, Frédérique
AU - Hoorne, Yana
AU - Joss, Shelagh
AU - Chassevent, Anna K.
AU - Smith-Hicks, Constance
AU - Loeys, Bart
AU - Joset, Pascal
AU - Steindl, Katharina
AU - Rauch, Anita
AU - Mehta, Sarju G.
AU - Chung, Wendy K.
AU - Devriendt, Koenraad
AU - Holder, Susan E.
AU - Jewett, Tamison
AU - Baldwin, Lauren M.
AU - Wilson, William G.
AU - Towner, Shelley
AU - Srivastava, Siddharth
AU - Johnson, Hannah F.
AU - Daumer-Haas, Cornelia
AU - Baethmann, Martina
AU - Ruiz, Anna
AU - Gabau, Elisabeth
AU - Jain, Vani
AU - Varghese, Vinod
AU - Al-Beshri, Ali
AU - Fulton, Stephen
AU - Wechsberg, Oded
AU - Orenstein, Naama
AU - Prescott, Katrina
AU - Childs, Anne Marie
AU - Faivre, Laurence
AU - Moutton, Sébastien
AU - Sullivan, Jennifer A.
AU - Shashi, Vandana
AU - Koudijs, Suzanne M.
AU - Heijligers, Malou
AU - Kivuva, Emma
AU - McTague, Amy
AU - Male, Alison
AU - van Ierland, Yvette
AU - Plecko, Barbara
AU - Maystadt, Isabelle
AU - Hamid, Rizwan
AU - Hannig, Vickie L.
AU - Houge, Gunnar
AU - Janssens, Veerle
N1 - Funding Information:
The authors thank the individuals and their parents for participating in the study. V.J. was funded by Jordan’s Guardian Angels Foundation; F.L. by Association pour le Développement de
Funding Information:
la Neurogénétique (INSERM) and French Ministry of Health (NCT01770548); A.R. by Swiss National Science Foundation. S. R. received an FWO-SB fellowship (Research Foundation- Flanders). Patient 23 was ascertained in the Duke Genome Sequencing Clinic as participant in a research study (Duke Protocol 00032301). Sequencing for this patient was performed
Funding Information:
at the Institute for Genomic Medicine, Columbia University (New York, NY, USA). Funding for the Duke Genome Sequencing Clinic is supported by Duke University Health System. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003). This study makes use of DECIPHER (http://decipher.sanger.ac.uk/), which is funded by Wellcome. A. McTague is supported by National Institute for Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, NIHR, or the UK Department of Health.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - epilepsy
KW - intellectual disability
KW - neurodevelopmental disorder
KW - PP2A
KW - PPP2R1A
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U2 - 10.1038/s41436-020-00981-2
DO - 10.1038/s41436-020-00981-2
M3 - Article
C2 - 33106617
AN - SCOPUS:85093843292
JO - Genetics in Medicine
JF - Genetics in Medicine
SN - 1098-3600
ER -