Familial Epilepsy Associated With Concurrent CHRNB2 Mutation and RBFOX1 Exon Deletion: A Case Report

Understanding the genetic basis of epilepsy may lead to an improved understanding of its etiology, more precise medical management, and ultimately improved outcomes. It is imperative for patients with epilepsy to obtain a molecular diagnosis, especially when strong familial epilepsy is discovered. We investigated a multi-generational family with epilepsy. The proband was a 19-year-old female who experienced focal onset seizures, with presenting symptoms of feeling dizzy, disorientation, and loss of consciousness. Her electroencephalography (EEG) studies revealed interictal focal slowing and sharp waves in both the left or right hemispheres independently. EEG monitoring showed that the seizures arose from the left fronto-temporal region and her brain MRI was normal. The proband's sister also suffered from focal onset seizures. Her EEG showed focal epileptiform discharge in the right temporal region, and her brain MRI was unrevealing. Two genetic tests were conducted for the proband: 1) array comparative genomic hybridization (CGH) revealed 16p13.3 deletion but no 22q deletion; and 2) next generation sequencing (NGS) Epilepsy Panel revealed a few variants of uncertain significance (VUS), including in CHRNB2 (c.1423A>G, p.Ile475Val) and RBFOX1 (RNA binding fox-1 homolog 1) (exon1-2 deletion). The proband’s sister also carries both the CHRNB2 (cholinergic receptor nicotinic beta 2) variant and RBFOX1 deletion. The proband’s father carries the CHRNB2 variant, and her brother and mother carry the deletion of RBFOX1. In this family, the co-expression of the CHRNB2 variant and RBFOX1 deletion may cause the clinical seizures seen in the proband and her sister. It is also possible that the RBFOX1 deletion is associated with an increased risk of seizure disorder with variable expressivity.