De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures

  • Am J Hum Genet. 2017 Oct 5;101(4):516-524. doi: 10.1016/j.ajhg.2017.08.013.
Candace T Myers  1 ,  Nicholas Stong  2 ,  Emily I Mountier  3 ,  Katherine L Helbig  4 ,  Saskia Freytag  5 ,  Joseph E Sullivan  6 ,  Bruria Ben Zeev  7 ,  Andreea Nissenkorn  7 ,  Michal Tzadok  7 ,  Gali Heimer  7 ,  Deepali N Shinde  4 ,  Arezoo Rezazadeh  8 ,  Brigid M Regan  8 ,  Karen L Oliver  9 ,  Michelle E Ernst  2 ,  Natalie C Lippa  2 ,  Maureen S Mulhern  2 ,  Zhong Ren  2 ,  Annapurna Poduri  10 ,  Danielle M Andrade  8 ,  Lynne M Bird  11 ,  Melanie Bahlo  5 ,  Samuel F Berkovic  12 ,  Daniel H Lowenstein  13 ,  Ingrid E Scheffer  14 ,  Lynette G Sadleir  3 ,  David B Goldstein  2 ,  Heather C Mefford  15 ,  Erin L Heinzen  16
Affiliations
  • 1. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
  • 2. Institute for Genomic Medicine, Columbia University Medical Center, New York, NY 10032, USA.
  • 3. Department of Paediatrics and Child Health, University of Otago, Wellington 6242, New Zealand.
  • 4. Ambry Genetics, Aliso Viejo, CA 92656, USA.
  • 5. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3050, Australia.
  • 6. Department of Neurology & Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 7. Sheba Medical Center, Ramat Gan, Israel, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
  • 8. Division of Neurology, Epilepsy Genetics Research Program, Toronto Western Hospital, Krembil Neuroscience Centre, University of Toronto, Toronto, ON M5T 2S8, Canada.
  • 9. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC 3084, Australia.
  • 10. Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital and Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
  • 11. Department of Pediatrics, University of California, San Diego, San Diego, CA 92037, USA; Rady Children's Hospital, San Diego, CA 92037, USA.
  • 12. Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC 3084, Australia.
  • 13. Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 14. Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC 3084, Australia; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, Parkville, VIC 3050, Australia.
  • 15. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. Electronic address: [email protected].
  • 16. Institute for Genomic Medicine, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: [email protected].
PMID: 28942967 DOI: 10.1016/j.ajhg.2017.08.013
Abstract

Exome Sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other neurodevelopmental diseases for which rare, often de novo, mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene. By pooling genetic findings across multiple studies, we have identified six individuals with severe developmental delay (6/6), refractory seizures (5/6), and similar dysmorphic features (3/6), each harboring a de novo mutation in PPP3CA. PPP3CA encodes the Alpha isoform of a subunit of Calcineurin. Calcineurin encodes a calcium- and calmodulin-dependent serine/threonine protein Phosphatase that plays a role in a wide range of biological processes, including being a key regulator of synaptic vesicle recycling at nerve terminals. Five individuals with de novo PPP3CA mutations were identified among 4,760 Trio probands with neurodevelopmental diseases; this is highly unlikely to occur by chance (p = 1.2 × 10-8) given the size and mutability of the gene. Additionally, a sixth individual with a de novo mutation in PPP3CA was connected to this study through GeneMatcher. Based on these findings, we securely implicate PPP3CA in early-onset refractory Epilepsy and further support the emerging role for synaptic dysregulation in Epilepsy.

Keywords
PPP3CA; calcineurin; de novo mutation; developmental and epileptic encephalopathy; epilepsy.