The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction
Lisa Lenaerts
(1)
,
Sara Reynhout
(1)
,
Iris Verbinnen
(1)
,
Frederic Laumonnier
(2, 3)
,
Annick Toutain
(2, 3)
,
Frédérique Bonnet-Brilhault
(2, 4)
,
Yana Hoorne
(1)
,
Shelagh Joss
(5)
,
Anna Chassevent
(6)
,
Constance Smith-Hicks
(6)
,
Bart Loeys
(7)
,
Pascal Joset
(8)
,
Katharina Steindl
(8)
,
Anita Rauch
(8)
,
Sarju Mehta
(9)
,
Wendy Chung
(10)
,
Koenraad Devriendt
(1)
,
Susan Holder
(11)
,
Tamison Jewett
(12)
,
Lauren Baldwin
(12)
,
William Wilson
(13)
,
Shelley Towner
(13)
,
Siddharth Srivastava
(14)
,
Hannah Johnson
(14)
,
Cornelia Daumer-Haas
(15)
,
Martina Baethmann
(16)
,
Anna Ruiz
(17)
,
Elisabeth Gabau
(17)
,
Vani Jain
(18)
,
Vinod Varghese
(18)
,
Ali Al-Beshri
(19)
,
Stephen Fulton
(20)
,
Oded Wechsberg
(21)
,
Naama Orenstein
(21, 22)
,
Katrina Prescott
(23)
,
Anne-Marie Childs
(23)
,
Laurence Faivre
(24)
,
Sébastien Moutton
(25)
,
Jennifer Sullivan
(26)
,
Vandana Shashi
(26)
,
Suzanne Koudijs
(27)
,
Malou Heijligers
(27)
,
Emma Kivuva
(28)
,
Amy Mctague
(29)
,
Alison Male
(29)
,
Yvette van Ierland
(30)
,
Barbara Plecko
(31)
,
Isabelle Maystadt
(32)
,
Rizwan Hamid
(33)
,
Vickie Hannig
(33)
,
Gunnar Houge
(34)
,
Veerle Janssens
(1, 35)
1
KU Leuven -
Catholic University of Leuven - Katholieke Universiteit Leuven
2 iBrain - Inserm U1253 - UNIV Tours - Imagerie et cerveau
3 Service de génétique [Tours]
4 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
5 Queen Elizabeth University Hospital (Glasgow)
6 Kennedy Krieger Institute [Baltimore]
7 UA - University of Antwerp
8 UZH - Universität Zürich [Zürich] = University of Zurich
9 Addenbrooke’s Hospital [Cambridge, UK]
10 CUMC - Columbia University Medical Center
11 Harrow - North West Thames Regional Genetics Service [London, UK]
12 Wake Forest University
13 University of Virginia
14 Boston Children's Hospital
15 PMM - Prenatal Medicine Munich [Munich, Germany]
16 Klinikum Dritter Orden [Munich]
17 UAB - Universitat Autònoma de Barcelona
18 UHW - University Hospital of Wales
19 UAB - University of Alabama at Birmingham [ Birmingham]
20 LBCH - Le Bonheur Children's Hospital [Memphis, TN, USA]
21 Schneider Children’s Medical Center of Israel [Petah Tikva]
22 Sackler Faculty of Medicine
23 Leeds Teaching Hospitals NHS Trust
24 Equipe GAD (LNC - U1231)
25 MSPB - Maison de Santé Protestante de Bordeaux-Bagatelle
26 Duke University Medical Center
27 MUMC - Maastricht University Medical Centre
28 Royal Devon and Exeter NHS Foundation Trust [UK]
29 UCL - Great Ormond Street Institute of Child Health
30 Erasmus MC - Erasmus University Medical Center [Rotterdam]
31 Medical University Graz
32 I.P.G. - Institut de Pathologie et Génétique [Gosselies]
33 Vanderbilt University Medical Center [Nashville]
34 Haukeland University Hospital
35 LBI - Leuven Brain Institute [Leuven, Belgium]
2 iBrain - Inserm U1253 - UNIV Tours - Imagerie et cerveau
3 Service de génétique [Tours]
4 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
5 Queen Elizabeth University Hospital (Glasgow)
6 Kennedy Krieger Institute [Baltimore]
7 UA - University of Antwerp
8 UZH - Universität Zürich [Zürich] = University of Zurich
9 Addenbrooke’s Hospital [Cambridge, UK]
10 CUMC - Columbia University Medical Center
11 Harrow - North West Thames Regional Genetics Service [London, UK]
12 Wake Forest University
13 University of Virginia
14 Boston Children's Hospital
15 PMM - Prenatal Medicine Munich [Munich, Germany]
16 Klinikum Dritter Orden [Munich]
17 UAB - Universitat Autònoma de Barcelona
18 UHW - University Hospital of Wales
19 UAB - University of Alabama at Birmingham [ Birmingham]
20 LBCH - Le Bonheur Children's Hospital [Memphis, TN, USA]
21 Schneider Children’s Medical Center of Israel [Petah Tikva]
22 Sackler Faculty of Medicine
23 Leeds Teaching Hospitals NHS Trust
24 Equipe GAD (LNC - U1231)
25 MSPB - Maison de Santé Protestante de Bordeaux-Bagatelle
26 Duke University Medical Center
27 MUMC - Maastricht University Medical Centre
28 Royal Devon and Exeter NHS Foundation Trust [UK]
29 UCL - Great Ormond Street Institute of Child Health
30 Erasmus MC - Erasmus University Medical Center [Rotterdam]
31 Medical University Graz
32 I.P.G. - Institut de Pathologie et Génétique [Gosselies]
33 Vanderbilt University Medical Center [Nashville]
34 Haukeland University Hospital
35 LBI - Leuven Brain Institute [Leuven, Belgium]
Frederic Laumonnier
- Function : Author
- PersonId : 13065
- IdHAL : frederic-laumonnier
- ORCID : 0000-0003-2567-0708
- IdRef : 085738026
Annick Toutain
- Function : Author
- PersonId : 825028
- ORCID : 0000-0002-5999-5300
- IdRef : 08130871X
Frédérique Bonnet-Brilhault
- Function : Author
- PersonId : 1003626
Wendy Chung
- Function : Author
- PersonId : 786377
- ORCID : 0000-0003-3438-5685
Laurence Faivre
- Function : Author
- PersonId : 757929
- ORCID : 0000-0001-9770-444X
Abstract
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.
Origin : Publication funded by an institution