Abstracts

Rationale: Migrating partial seizures of infancy (MPSI) is a severe, early onset epileptic encephalopathy characterised by frequent and intractable focal seizures and developmental delay. KCNT1 encodes a sodium activated potassium channel and is a recently described cause of MPSI. We evaluated our UK cohort of patients with MPSI for mutations in KCNT1.Methods: Patients were recruited via a national surveillance study and detailed phenotyping was performed to delineate clinical, EEG, radiological and pathological features. A combined strategy of whole exome sequencing (Illumina paired-end library preparation and sequencing on a Hi-Seq platform) and direct Sanger sequencing was employed for molecular genetic investigation. For Sanger sequencing, the genomic KCNT1 DNA sequence was taken from Ensembl and primer pairs for all exons and flanking intronic regions were designed using primer3 software. Exons were amplified by PCR, sequenced by the BigDye terminator method and analysed with Chromas/Sequencher software. Results: Fourteen patients met the electroclinical criteria for a diagnosis of MPSI. Two different missense mutations were identified in 30% of patients tested. One mutation (c.2800G>A, p.A934T) was found in several patients and has been previously reported. Another mutation (c.811G>T, p.V271F) is a novel, previously unreported variant. These mutations are not seen in 1000 Genomes or other databases of genetic variation. Amino acid residues affected by these variants were highly conserved throughout species.Conclusions: KCNT1 is a significant disease-causing gene in MPSI. However as we have demonstrated, this condition is genetically heterogeneous and further genetic aetiologies are yet to be discovered. Given the genetic heterogeneity of EIEE, the phenotypic spectrum of KCNT1 is likely to extend beyond this specific electroclinical syndrome.