2. Academic Validation
  3. De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures

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

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: hmefford@uw.edu.
  • 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: eh2682@cumc.columbia.edu.
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.

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