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The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction.

Publication ,  Journal Article
Lenaerts, L; Reynhout, S; Verbinnen, I; Laumonnier, F; Toutain, A; Bonnet-Brilhault, F; Hoorne, Y; Joss, S; Chassevent, AK; Smith-Hicks, C ...
Published in: Genet Med
February 2021

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.

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Published In

Genet Med

DOI

EISSN

1530-0366

Publication Date

February 2021

Volume

23

Issue

2

Start / End Page

352 / 362

Location

United States

Related Subject Headings

  • Transcription Factors
  • Protein Phosphatase 2
  • Neurodevelopmental Disorders
  • Muscle Hypotonia
  • Microcephaly
  • Intellectual Disability
  • Humans
  • Genetics & Heredity
  • 3105 Genetics
  • 1103 Clinical Sciences
 

Citation

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Lenaerts, L., Reynhout, S., Verbinnen, I., Laumonnier, F., Toutain, A., Bonnet-Brilhault, F., … Janssens, V. (2021). The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction. Genet Med, 23(2), 352–362. https://doi.org/10.1038/s41436-020-00981-2
Lenaerts, Lisa, Sara Reynhout, Iris Verbinnen, Frédéric Laumonnier, Annick Toutain, Frédérique Bonnet-Brilhault, Yana Hoorne, et al. “The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction.Genet Med 23, no. 2 (February 2021): 352–62. https://doi.org/10.1038/s41436-020-00981-2.
Lenaerts L, Reynhout S, Verbinnen I, Laumonnier F, Toutain A, Bonnet-Brilhault F, et al. The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction. Genet Med. 2021 Feb;23(2):352–62.
Lenaerts, Lisa, et al. “The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction.Genet Med, vol. 23, no. 2, Feb. 2021, pp. 352–62. Pubmed, doi:10.1038/s41436-020-00981-2.
Lenaerts L, Reynhout S, Verbinnen I, Laumonnier F, Toutain A, Bonnet-Brilhault F, Hoorne Y, Joss S, Chassevent AK, Smith-Hicks C, Loeys B, Joset P, Steindl K, Rauch A, Mehta SG, Chung WK, Devriendt K, Holder SE, Jewett T, Baldwin LM, Wilson WG, Towner S, Srivastava S, Johnson HF, Daumer-Haas C, Baethmann M, Ruiz A, Gabau E, Jain V, Varghese V, Al-Beshri A, Fulton S, Wechsberg O, Orenstein N, Prescott K, Childs A-M, Faivre L, Moutton S, Sullivan JA, Shashi V, Koudijs SM, Heijligers M, Kivuva E, McTague A, Male A, van Ierland Y, Plecko B, Maystadt I, Hamid R, Hannig VL, Houge G, Janssens V. The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction. Genet Med. 2021 Feb;23(2):352–362.

Published In

Genet Med

DOI

EISSN

1530-0366

Publication Date

February 2021

Volume

23

Issue

2

Start / End Page

352 / 362

Location

United States

Related Subject Headings

  • Transcription Factors
  • Protein Phosphatase 2
  • Neurodevelopmental Disorders
  • Muscle Hypotonia
  • Microcephaly
  • Intellectual Disability
  • Humans
  • Genetics & Heredity
  • 3105 Genetics
  • 1103 Clinical Sciences