A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability

Mutations in the KCNQ2 gene encoding for voltage-gated potassium channel subunitshave been found in patients affected with early onset epilepsies with wide phenotypicheterogeneity, ranging from benign familial neonatal seizures (BFNS) to epilepticencephalopathy with cognitive impairment, drug resistance, and characteristic elec-troencephalography(EEG)andneuroradiologicfeatures.Bycontrast,onlyfewKCNQ3mutations have been rarely described, mostly in patients with typical BFNS. Wereport clinical, genetic, and functional data from a family in which early onset epilepsyand neurocognitive deficits segregated with a novel mutation in KCNQ3 (c.989G>T;p.R330L).Electrophysiologicalstudiesinmammaliancellsrevealedthatincorporationof KCNQ3 R330L mutant subunits impaired channel function, suggesting a pathoge-neticroleforsuchmutation.Thedegreeoffunctionalimpairmentofchannelsincorpo-rating KCNQ3 R330L subunits was larger than that of channels carrying anotherKCNQ3mutationaffectingthesamecodonbutleadingtoadifferentaminoacidsubsti-tution (p.R330C), previously identified in two families with typical BFNS. These datasuggest that mutations in KCNQ3, similarly to KCNQ2, can be found in patients withmore severe phenotypes including intellectual disability, and that the degree of thefunctional impairment caused by mutations at position 330 in KCNQ3 may contributetoclinicaldiseaseseverity.KEY WORDS: Benign familial neonatal seizures, KCNQ, Cognitive impairment, Volt-age-gated potassium channels, Epilepsy, Mutagenesis, Genotype-phenotype correlations.