Abstracts

Rationale: Understanding the genetic basis of epilepsy may lead to improved understanding the etiology, a precision medical management and ultimately improved outcomes. It is imperative for patients with epilepsy to obtain a molecular diagnosis, especially when a strong familiar epilepsy is discovered. Variants in CHRNB2 has been studied and linked to autosomal dominant nocturnal frontal lobe epilepsy. Partial deletions of the RBFOX1 gene encoding the neuronal splicing regulator have been reported in a wide range of neurodevelopmental disorders. This case report describes a multi-generation family with epilepsy was identified with CHRNB2 gene mutation and RBFOX1 exon deletion.

Methods: The proband and her sister were studied with EEG, brain imaging and molecular genetic analyses. The medical information and genetic tests were obtained from the other multi-generation family members.

Results: The proband, her maternal aunt and maternal cousin had adult-onset focal or generalized seizures (Figure 1), the proband sister has teenager onset focal impaired seizures. The proband was 19-yo when experienced first seizures. Thereafter, she continued with episodes of feeling dizzy, disoriented and passing out. Episodes lasted 30-60 sec. She was amnestic to some of her spells. She underwent video EEG monitoring; focal slow and sharp waves were seen in either left or right centro-parietal regions. One focal non-impaired seizure, arising from the left fronto-temporal regions, was recorded. Her brain MRI was normal. The proband sister’s EEG showed focal epileptiform discharge in the right temporal regions, and brain MRI was unrevealing. The proband genetic tests were conducted (1) array CGH revealed 16p13.3 deletion but no 22q deletion; and (2) NGS Epilepsy Panel revealed a few variants of uncertain significance (VUS): CHRNB2 (c.1423A >G, p.Ile475Val), RBFOX1 (exon1-2 deletion), SYNJ1, PCLO, PEX10, QARS (Table 1). The proband sister also carries both CHRNB2 variant and RBFOX1 deletion. Proband father carries CHRNB2 variant; her brother and her mother carry the deletion of RBFOX1. None of the carriers have seizures. The maternal aunt and cousin who had seizures were not tested. Another maternal cousin and her son were discovered 22q deletion syndrome with birth organ defect, such information was thought irrelevant to the familiar epilepsy. Applying Alphafold AI and deep learning, it revealed that the CHRNB2 VUS not likely impacts the protein structure (Table 1, inserted figure), which endorsed that such VUS unlikely causes familiar epilepsy. _x000D_
Conclusions: In this family, the RBFOX1 deletion is possibility associated with an increased risk of seizure disorder with variable expressivity. It is also possible that the co-expression of CHRNB2 variant and RBFOX1 deletion may cause the clinical seizures seen in the proband and her sister. Our data highlights the need to increase awareness of and access to genetic testing for adult epilepsy patients with family history. Genetic findings will also provide valuable insight into the natural history of epilepsy heterogeneity.

Funding: None