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Am J Hum Genet. 2017 Oct 5;101(4):516-524. doi: 10.1016/j.ajhg.2017.08.013. Epub 2017 Sep 21.

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

Author information

1
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
2
Institute for Genomic Medicine, Columbia University Medical Center, New York, NY 10032, USA.
3
Department of Paediatrics and Child Health, University of Otago, Wellington 6242, New Zealand.
4
Ambry Genetics, Aliso Viejo, CA 92656, USA.
5
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3050, Australia.
6
Department of Neurology & Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
7
Sheba Medical Center, Ramat Gan, Israel, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
8
Division of Neurology, Epilepsy Genetics Research Program, Toronto Western Hospital, Krembil Neuroscience Centre, University of Toronto, Toronto, ON M5T 2S8, Canada.
9
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC 3084, Australia.
10
Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital and Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
11
Department of Pediatrics, University of California, San Diego, San Diego, CA 92037, USA; Rady Children's Hospital, San Diego, CA 92037, USA.
12
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC 3084, Australia.
13
Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
14
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC 3084, Australia; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, Parkville, VIC 3050, Australia.
15
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. Electronic address: hmefford@uw.edu.
16
Institute for Genomic Medicine, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: eh2682@cumc.columbia.edu.

Abstract

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

PMID:
28942967
PMCID:
PMC5630160
DOI:
10.1016/j.ajhg.2017.08.013
[Indexed for MEDLINE]
Free PMC Article

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