5 years ago

De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures

De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures
Saskia Freytag, Emily I. Mountier, Annapurna Poduri, Heather C. Mefford, Joseph E. Sullivan, Karen L. Oliver, David B. Goldstein, Melanie Bahlo, Arezoo Rezazadeh, Lynette G. Sadleir, Katherine L. Helbig, Michal Tzadok, Gali Heimer, Ingrid E. Scheffer, Danielle M. Andrade, Candace T. Myers, Brigid M. Regan, Zhong Ren, Nicholas Stong, Andreea Nissenkorn, Michelle E. Ernst, Deepali N. Shinde, Samuel F. Berkovic, Bruria Ben Zeev, Natalie C. Lippa, Erin L. Heinzen, Maureen S. Mulhern, Daniel H. Lowenstein, Lynne M. Bird

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.

Publisher URL: http://www.cell.com/ajhg/fulltext/S0002-9297(17)30335-X

DOI: 10.1016/j.ajhg.2017.08.013

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