De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures

Candace T. Myers, Nicholas Stong, Emily I. Mountier, Katherine L. Helbig, Saskia Freytag, Joseph E. Sullivan, Bruria Ben Zeev, Andreea Nissenkorn, Michal Tzadok, Gali Heimer, Deepali N. Shinde, Arezoo Rezazadeh, Brigid M. Regan, Karen L. Oliver, Michelle E. Ernst, Natalie C. Lippa, Maureen S. Mulhern, Zhong Ren, Annapurna Poduri, Danielle M. AndradeLynne M. Bird, Melanie Bahlo, Samuel F. Berkovic, Daniel H. Lowenstein, Ingrid E. Scheffer, Lynette G. Sadleir, David B. Goldstein, Heather C. Mefford*, Erin L. Heinzen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)516-524
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - 5 Oct 2017


FundersFunder number
Australian Government NHMRC
Australian National Health and Medical Research CouncilAPP1102971, APP1054618
Cure Kids New Zealand
Lennox-Gaustaut Syndrome Foundation
Victorian State Government
National Institute of Neurological Disorders and StrokeU01NS077303, RO1 NS069605, U01NS053998
National Institute of Neurological Disorders and Stroke
American Epilepsy Society
Health Research Council of New Zealand


    • PPP3CA
    • calcineurin
    • de novo mutation
    • developmental and epileptic encephalopathy
    • epilepsy


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