PPP3CA truncating variants clustered in the regulatory domain cause early-onset refractory epilepsy

Undiagnosed Diseases Network, the DDD Study

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


PPP3CA encodes the catalytic subunit of calcineurin, a calcium-calmodulin-regulated serine–threonine phosphatase. Loss-of-function (LoF) variants in the catalytic domain have been associated with epilepsy, while gain-of-function (GoF) variants in the auto-inhibitory domain cause multiple congenital abnormalities. We herein report five new patients with de novo PPP3CA variants. Interestingly, the two frameshift variants in this study and the six truncating variants reported previously are all located within a 26-amino acid region in the regulatory domain (RD). Patients with a truncating variant had more severe earlier onset seizures compared to patients with a LoF missense variant, while autism spectrum disorder was a more frequent feature in the latter. Expression studies of a truncating variant showed apparent RNA expression from the mutant allele, but no detectable mutant protein. Our data suggest that PPP3CA truncating variants clustered in the RD, causing more severe early-onset refractory epilepsy and representing a type of variants distinct from LoF or GoF missense variants.

Original languageEnglish
Pages (from-to)227-233
Number of pages7
JournalClinical Genetics
Issue number2
StatePublished - Aug 2021
Externally publishedYes


  • calcineurin
  • constitutive activation
  • epileptic syndromes
  • gain-of-function
  • loss-of-function
  • truncating variants


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