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. Epub 2017 Sep 21.


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.

MeSH terms

  • Adolescent
  • Adult
  • Calcineurin / genetics*
  • Calcineurin / metabolism
  • Child
  • Child, Preschool
  • Cohort Studies
  • Epilepsy / genetics*
  • Epilepsy / pathology
  • Exome / genetics
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Lennox Gastaut Syndrome / pathology
  • Male
  • Mutation*
  • Neurodevelopmental Disorders / genetics*
  • Neurodevelopmental Disorders / pathology
  • Sequence Analysis, DNA
  • Severity of Illness Index
  • Spasms, Infantile / genetics
  • Spasms, Infantile / pathology
  • Synaptic Transmission / physiology*
  • Young Adult


  • Calcineurin
  • PPP3CA protein, human

Supplementary concepts

  • Epileptic encephalopathy, Lennox-Gastaut type
  • Infantile Epileptic-Dyskinetic Encephalopathy