%0 Journal Article
%T De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures
%A Andreea Nissenkorn
%A Annapurna Poduri
%A Arezoo Rezazadeh
%A Brigid M. Regan
%A Bruria Ben Zeev
%A Candace T. Myers
%A Daniel H. Lowenstein
%A Danielle M. Andrade
%A David B. Goldstein
%A Deepali N. Shinde
%A Emily I. Mountier
%A Erin L. Heinzen
%A Gali Heimer
%A Heather C. Mefford
%A Ingrid E. Scheffer
%A Joseph E. Sullivan
%A Karen L. Oliver
%A Katherine L. Helbig
%A Lynette G. Sadleir
%A Lynne M. Bird
%A Maureen S. Mulhern
%A Michal Tzadok
%A Michelle E. Ernst
%A Natalie C. Lippa
%A Nicholas Stong
%A Samuel F. Berkovic
%A Saskia Freytag
%A Zhong Ren
%J Archive of "American Journal of Human Genetics".
%D 2017
%R 10.1016/j.ajhg.2017.08.013
%X 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 ¡Á 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
%K developmental and epileptic encephalopathy
%K epilepsy
%K de novo mutation
%K PPP3CA
%K calcineurin
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630160/