De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures.


Journal Article

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.

Full Text

Cited Authors

  • Myers, CT; Stong, N; Mountier, EI; Helbig, KL; Freytag, S; Sullivan, JE; Ben Zeev, B; Nissenkorn, A; Tzadok, M; Heimer, G; Shinde, DN; Rezazadeh, A; Regan, BM; Oliver, KL; Ernst, ME; Lippa, NC; Mulhern, MS; Ren, Z; Poduri, A; Andrade, DM; Bird, LM; Bahlo, M; Berkovic, SF; Lowenstein, DH; Scheffer, IE; Sadleir, LG; Goldstein, DB; Mefford, HC; Heinzen, EL

Published Date

  • October 2017

Published In

Volume / Issue

  • 101 / 4

Start / End Page

  • 516 - 524

PubMed ID

  • 28942967

Pubmed Central ID

  • 28942967

Electronic International Standard Serial Number (EISSN)

  • 1537-6605

International Standard Serial Number (ISSN)

  • 0002-9297

Digital Object Identifier (DOI)

  • 10.1016/j.ajhg.2017.08.013


  • eng