De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy.
BACKGROUND
Mutations of SCN8A encoding the neuronal voltage-gated sodium channel NaV1.6 are associated with early-infantile epileptic encephalopathy type 13 (EIEE13) and intellectual disability. Using clinical exome sequencing, we have detected three novel de novo SCN8A mutations in patients with intellectual disabilities, and variable clinical features including seizures in two patients. To determine the causality of these SCN8A mutations in the disease of those three patients, we aimed to study the (dys)function of the mutant sodium channels.


METHODS
The functional consequences of the three SCN8A mutations were assessed using electrophysiological analyses in transfected cells. Genotype-phenotype correlations of these and other cases were related to the functional analyses.


RESULTS
The first mutant displayed a 10 mV hyperpolarising shift in voltage dependence of activation (gain of function), the second did not form functional channels (loss of function), while the third mutation was functionally indistinguishable from the wildtype channel.


CONCLUSIONS
Comparison of the clinical features of these patients with those in the literature suggests that gain-of-function mutations are associated with severe EIEE, while heterozygous loss-of-function mutations cause intellectual disability with or without seizures. These data demonstrate that functional analysis of missense mutations detected by clinical exome sequencing, both inherited and de novo, is valuable for clinical interpretation in the age of massive parallel sequencing.
Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Maxime G
MG
Blanchard
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Marjolein H
MH
Willemsen
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
Jaclyn B
JB
Walker
The Center for Neuroscience & Regeneration Research, Yale School of Medicine, New Haven, Connecticut, USA The Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, Connecticut, USA.
Sulayman D
SD
Dib-Hajj
The Center for Neuroscience & Regeneration Research, Yale School of Medicine, New Haven, Connecticut, USA The Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, Connecticut, USA.
Stephen G
SG
Waxman
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Marjolijn C J
MC
Jongmans
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Tjitske
T
Kleefstra
Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
Bart P
BP
van de Warrenburg
Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
Peter
P
Praamstra
Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands Epilepsy Center Kempenhaeghe, Heeze, The Netherlands.
Joost
J
Nicolai
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Helger G
HG
Yntema
Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
René J M
RJ
Bindels
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
Miriam H
MH
Meisler
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Erik-Jan
EJ
Kamsteeg
D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002460:Cell Line; D002648:Child; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D009154:Mutation; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D021122:Protein Subunits / Q000235:genetics
D062557:NAV1.6 Voltage-Gated Sodium Channel; D021122:Protein Subunits; C100681:SCN8A protein, human
Epilepsy and seizures; Movement disorders (other than Parkinsons); encephalopathy; intelectual disability; sodium channel