De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy.
J Med Genet
; 52(5): 330-7, 2015 May.
Article
in En
| MEDLINE
| ID: mdl-25725044
ABSTRACT
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Epilepsy
/
Genetic Association Studies
/
NAV1.6 Voltage-Gated Sodium Channel
/
Intellectual Disability
/
Mutation
Type of study:
Diagnostic_studies
/
Prognostic_studies
Limits:
Adult
/
Child
/
Female
/
Humans
/
Male
Language:
En
Journal:
J Med Genet
Year:
2015
Type:
Article
Affiliation country:
Netherlands