De novo gain-of-function variants in KCNT2 as a novel cause of developmental and epileptic encephalopathy.


Ambrosino P1, Soldovieri MV1, Bast T2,3, Turnpenny PD4, Uhrig S5, Biskup S6, Döcker M6, Fleck T7, Mosca I1, Manocchio L1, Iraci N8, Taglialatela M9, Lemke JR10
  1. Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, Italy.
  2. Epilepsy Center Kork, Kehl, Germany.
  3. Faculty of Medicine of the University of Freiburg, Freiburg, Germany.
  4. Clinical Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, United Kingdom.
  5. Institute of Clinical Genetics, Klinikum Stuttgart, Stuttgart, Germany.
  6. CeGaT GmbH and Praxis für Humangenetik Tübingen, Tübingen, Germany.
  7. University Heart Center Freiburg-Bad Krozingen, Department of Congenital Heart Disease and Pediatric Cardiology, Medical Center-University of Freiburg, Freiburg, Germany.
  8. Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
  9. Department of Neuroscience, University of Naples “Federico II”, Naples, Italy.
  10. Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.


Variants in several potassium channel genes have been found in developmental and epileptic encephalopathies (DEE). We report on 2 females with de novo variants in KCNT2 with West syndrome followed by Lennox-Gastaut syndrome or with DEE with migrating focal seizures. After in vitro analysis suggested quinidine-responsive gain-of-function effects, we treated 1 of the girls with quinidine add-on therapy and achieved marked clinical improvements. This suggests that the new spectrum of KCNT2-related disorders do not only share similar phenotypic and in vitro functional and pharmacological features with previously known KCNT1-related disorders, but also represents a further example for possible precision medicine approaches. Ann Neurol 2018;83:1198-1204.