Genotype-phenotype associations in SCN1A-related epilepsies.
OBJECTIVE
Most mutations in SCN1A-related epilepsies are novel and when an infant presents with febrile seizures (FS) it is uncertain if they will have simple FS, FS+, or develop a severe epilepsy such as Dravet syndrome. Our objective was to examine whether the nature of a SCN1A mutation affects the epilepsy phenotype.


METHODS
We retrospectively evaluated clinical and genetic data from 273 individuals with SCN1A mutations identified in our laboratory and reviewed data from 546 published cases. We examined whether the mutation class or distribution or nature of amino acid substitution correlated with the epilepsy phenotype, using the Grantham Score (GS) as a measure of physicochemical difference between amino acids.


RESULTS
Compared to missense mutations, truncating mutations were associated with earlier mean onset of prolonged seizures (7.4 vs 8.8 months; p = 0.040), myoclonic seizures (16.4 vs 19.4 months; p = 0.041), and atypical absence seizures (19.1 vs 30.6 months; p = 0.001). The median GS was higher in patients with Dravet syndrome compared to polymorphisms (94 vs 58; p = 0.029) and orthologs (94 vs 45; p < 0.001). A high GS was correlated with early onset of seizures (r(s) = -0.235; p = 0.008). Missense mutations occurred most frequently in the voltage and ion-pore regions where changes in amino acid polarity were greater in the Dravet group compared to the genetic epilepsy with febrile seizures plus group (3.6 vs 2.7; p = 0.031).


CONCLUSIONS
These findings help define the clinical significance of specific SCN1A mutations based on mutation class and amino acid property and location.
Royal Hospital for Sick Children, Yorkhill, Glasgow G3 8SJ, UK. sameer.zuberi@nhs.net
S M
SM
Zuberi
A
A
Brunklaus
R
R
Birch
E
E
Reavey
J
J
Duncan
G H
GH
Forbes
D017668:Age of Onset; D015331:Cohort Studies; D004829:Epilepsy, Generalized / Q000150:complications / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D009154:Mutation / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012189:Retrospective Studies; D003294:Seizures, Febrile / Q000150:complications / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics*; D018709:Statistics, Nonparametric
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels