• Tariq Zaman
  • Katherine L Helbig
  • Jérôme Clatot
  • Christopher H Thompson
  • Seok Kyu Kang
  • Lieve Verstraete
  • Adeline Jacquinet
  • Elena Parrini
  • Renzo Guerrini
  • Yuh Fujiwara
  • Satoko Miyatake
  • Bruria Ben-Zeev
  • Haim Bassan
  • Orit Reish
  • Daphna Marom
  • Natalie Hauser
  • Thuy-Anh Vu
  • Sally Ackermann
  • Careni E Spencer
  • Natalie Lippa
  • Shraddha Srinivasan
  • Agnieszka Charzewska
  • Dorota Hoffman-Zacharska
  • David Fitzpatrick
  • Victoria Harrison
  • Pradeep Vasudevan
  • Shelagh Joss
  • Daniela T Pilz
  • Katherine A Fawcett
  • Ingo Helbig
  • Naomichi Matsumoto
  • Jennifer A Kearney
  • Andrew E Fry
  • Ethan M Goldberg

OBJECTIVE: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood-onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder.

METHODS: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type vs. variant Nav1.3 subunits co-expressed with β1 and β2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293 T cells).

RESULTS: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20; 75%). Many, but not all (15/19; 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4-6 of domains II-IV. Most pathogenic missense variants tested (10/11; 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function.

INTERPRETATION: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in over 75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis.

Original languageEnglish
Pages (from-to)348-362
Number of pages15
JournalAnnals of Neurology
Issue number2
Early online date8 Jun 2020
Publication statusPublished - 1 Aug 2020

ID: 52537207