CHRNA4 variant causes paroxysmal kinesigenic dyskinesia and genetic epilepsy with febrile seizures plus?

PURPOSE: Paroxysmal kinesigenic dyskinesia (PKD) and epilepsy are thought to have a shared genetic etiology. PRRT2 has been identified as a causative gene of both disorders. In this study, we aim to explore the potential novel causative gene in a PRRT2-negative family with three individuals diagnosed with PKD or genetic epilepsy with febrile seizures plus (GEFS+).

METHODS: Clinical data were collected from all the affected and unaffected members of a PKD/GEFS+ family. The Brain magnetic resonance imaging and 24 h video-EEG of all three affected members were analyzed. Targeted gene-panel sequencing was used to detect the genetic defect in genomic DNAs of three affected and five normal individuals. Co-segregation analysis of putatively pathogenic mutations with the phenotype was carried out in all the family members alive to examine the inheritance status.

RESULTS: The inheritance model of this pedigree was autosomal dominant. A novel, fully co-segregated mutation (NM_000744: c.979G > A) in CHRNA4 was identified in the family with three individuals diagnosed with PKD or GEFS+.

CONCLUSIONS: CHRNA4 may be a novel gene causing of PKD and GEFS+. Our study extends the genotypic-phenotypic spectrum of combined epileptic and dyskinetic syndromes, and provides a genetic linkage between PKD and GEFS+.