Alterations of functional connectivity density in a Chinese family with a mild phenotype associated with a novel inherited variant of SCN8A

Objective: Only a few heritable SCN8A variants have been described in patients with a mild phenotype of epilepsy. Here, we describe a Chinese family with a novel inherited SCN8A variant and investigate changes in spontaneous cerebral activity during the resting-state in magnetic resonance imaging (MRI)-negative patients with epilepsy and their unaffected siblings.

Methods: A gene panel targeting 535 epilepsy genes was performed on the proband and his parents. The identified variant was confirmed in other affected members by Sanger sequencing. Resting-state functional MRI (fMRI) data were gathered from the family (4 affected individuals and 3 unaffected siblings) and 72 healthy controls (HCs). Functional connectivity density (FCD) was used to assess whether distant or local functional network changes occurred in patients with epilepsy.

Results: A heterozygous missense variant (c.4568C>A; p.A1523D) in SCN8A was identified in the Chinese family, with a total of 7 members who presented with a mild phenotype (childhood seizures and normal cognition). All patients remained seizure-free, and one patient remained seizure-free without medication. Increased FCD values in the thalamocortical network and basal ganglia network were observed in both patients with epilepsy and their unaffected siblings compared with the HCs. Direct comparison between SCN8A variant patients and unaffected siblings showed that more serious and distributed abnormal changes occurred in the mesial frontal regions of patients with epilepsy.

Conclusions: We identified a novel SCN8A variant with a mild familial epilepsy phenotype. A similar pattern of FCD alterations in patients and their unaffected siblings might represent an endophenotype of benign epilepsy associated with the SCN8A inherited variant, and more extensive alterations in mesial frontal regions may help us to further understand the pathogenesis of SCN8A-related mild epilepsy.