The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction |
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| Institution: | 1. Laboratory of Protein Phosphorylation & Proteomics, Department of Cellular & Molecular Medicine, University of Leuven (KU Leuven), Leuven, Belgium;;2. KU Leuven Brain Institute (LBI), Leuven, Belgium;;3. UMR1253, iBrain, University of Tours, INSERM, Tours, France,;4. Service de Génétique, Centre Hospitalier Régional Universitaire, Tours, France;;5. Excellence Center in Autism and Neurodevelopmental Disorders, Centre Hospitalier Régional Universitaire, Tours, France,;6. West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, UK;;7. Kennedy Krieger Institute, Baltimore, MD, USA;;8. Center for Medical Genetics, University of Antwerp/Antwerp University Hospital, Antwerp, Belgium;;9. Institute of Medical Genetics, University of Zurich, Schlieren, Zurich, Switzerland,;10. East Anglian Regional Medical Genetics Service, Addenbrookes Hospital, Cambridge, UK,;11. Columbia University Medical Center, New York, NY, USA,;12. Department of Human Genetics, University of Leuven (KU Leuven), Leuven, Belgium,;13. North West Thames Regional Genetics Service, Harrow, London, UK;;14. Wake Forest School of Medicine, Wake Forest University, Winston-Salem, NC, USA;;15. Department of Pediatrics, University of Virginia, Charlottesville, VA, USA;;16. Department of Neurology, Boston Children’s Hospital, Boston, MA, USA,;17. Prenatal Medicine Munich, Munich, Germany;;18. Pediatric Neurology, Sozialpädiatrisches Zentrum, Klinikum Dritter Orden München, Munich, Germany;;19. Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain;;20. Paediatric Unit, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain;;21. All Wales Medical Genomics Service, University Hospital of Wales, Cardiff, UK,;22. Internal Medicine & Medical Genetics, University of Alabama at Birmingham, Birmingham, AL, USA;;23. Le Bonheur Children’s Hospital, Memphis, TN, USA,;24. Pediatric Genetics Unit, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel;;25. Maccabi Healthcare Services, Tel Aviv, Israel;;26. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;;27. Yorkshire Regional Genetics Department, Leeds Teaching Hospitals NHS Trust, Leeds, UK,;28. Department of Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK,;29. Centre de référence Anomalies du Développement et Syndromes malformatifs, FHU TRANSLAD, UMR1231 GAD, CHU Dijon et Université de Bourgogne, Dijon, France,;30. CPDPN, Pôle mère enfant, Maison de Santé Bordeaux Bagatelle, Talence, France;;31. Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA;;32. Maastricht UMC+, Maastricht, The Netherlands,;33. Department of Clinical Genetics, Maastricht UMC+, Maastricht, The Netherlands,;34. Royal Devon & Exeter NHS Foundation Trust, Exeter, UK,;35. Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK;;36. Department of Neurology, Great Ormond Street Hospital, London, UK;;37. Erasmus MC, Department of Clinical Genetics, Rotterdam, The Netherlands;;38. Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria,;39. Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium,;40. Vanderbilt University Medical Center, Nashville, TN, USA,;41. Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway,;1. Laboratory of Protein Phosphorylation & Proteomics, Department of Cellular & Molecular Medicine, University of Leuven (KU Leuven), Leuven, Belgium;;2. KU Leuven Brain Institute (LBI), Leuven, Belgium;;3. UMR1253, iBrain, University of Tours, INSERM, Tours, France,;4. Service de Génétique, Centre Hospitalier Régional Universitaire, Tours, France;;5. Excellence Center in Autism and Neurodevelopmental Disorders, Centre Hospitalier Régional Universitaire, Tours, France,;6. West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, UK;;7. Kennedy Krieger Institute, Baltimore, MD, USA;;8. Center for Medical Genetics, University of Antwerp/Antwerp University Hospital, Antwerp, Belgium;;9. Institute of Medical Genetics, University of Zurich, Schlieren, Zurich, Switzerland,;10. East Anglian Regional Medical Genetics Service, Addenbrookes Hospital, Cambridge, UK,;11. Columbia University Medical Center, New York, NY, USA,;12. Department of Human Genetics, University of Leuven (KU Leuven), Leuven, Belgium,;13. North West Thames Regional Genetics Service, Harrow, London, UK;;14. Wake Forest School of Medicine, Wake Forest University, Winston-Salem, NC, USA;;15. Department of Pediatrics, University of Virginia, Charlottesville, VA, USA;;16. Department of Neurology, Boston Children’s Hospital, Boston, MA, USA,;17. Prenatal Medicine Munich, Munich, Germany;;18. Pediatric Neurology, Sozialpädiatrisches Zentrum, Klinikum Dritter Orden München, Munich, Germany;;19. Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain;;20. Paediatric Unit, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain;;21. All Wales Medical Genomics Service, University Hospital of Wales, Cardiff, UK,;22. Internal Medicine & Medical Genetics, University of Alabama at Birmingham, Birmingham, AL, USA;;23. Le Bonheur Children’s Hospital, Memphis, TN, USA,;24. Pediatric Genetics Unit, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel;;25. Maccabi Healthcare Services, Tel Aviv, Israel;;26. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;;27. Yorkshire Regional Genetics Department, Leeds Teaching Hospitals NHS Trust, Leeds, UK,;28. Department of Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK,;29. Centre de référence Anomalies du Développement et Syndromes malformatifs, FHU TRANSLAD, UMR1231 GAD, CHU Dijon et Université de Bourgogne, Dijon, France,;30. CPDPN, Pôle mère enfant, Maison de Santé Bordeaux Bagatelle, Talence, France;;31. Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA;;32. Maastricht UMC+, Maastricht, The Netherlands,;33. Department of Clinical Genetics, Maastricht UMC+, Maastricht, The Netherlands,;34. Royal Devon & Exeter NHS Foundation Trust, Exeter, UK,;35. Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK;;36. Department of Neurology, Great Ormond Street Hospital, London, UK;;37. Erasmus MC, Department of Clinical Genetics, Rotterdam, The Netherlands;;38. Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria,;39. Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium,;40. Vanderbilt University Medical Center, Nashville, TN, USA,;41. Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway, |
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| Abstract: | PurposeNeurodevelopmental 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.MethodsMost cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits.ResultsWe 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.ConclusionWe 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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