Dataset Information

An SCN1A gene missense variant in a Chinese Tujia ethnic family with genetic epilepsy with febrile seizures plus.

ABSTRACT: Genetic epilepsy with febrile seizures plus (GEFSP) is a familial epileptic syndrome that is genetically heterogeneous and inherited in an autosomal dominant form in most cases. To date, at least seven genes have been reported to associate with GEFSP. This study aimed to identify the disease-causing variant in a Chinese Tujia ethnic family with GEFSP by using whole exome sequencing, Sanger sequencing, and in silico prediction. A heterozygous missense variant c.5725A>G (p.T1909A) was identified in the sodium voltage-gated channel alpha subunit 1 gene (SCN1A) coding region. The variant co-segregated with the GEFSP phenotype in this family, and it was predicted as disease-causing by multiple in silico programs, which was proposed as the genetic cause of GEFSP, further genetically diagnosed as GEFSP2. These findings expand the genetic and phenotypic spectrum of GEFSP and should contribute to genetic diagnoses, personalized therapies, and prognoses.

SUBMITTER: Li L

PROVIDER: S-EPMC10412811 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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An <i>SCN1A</i> gene missense variant in a Chinese Tujia ethnic family with genetic epilepsy with febrile seizures plus.

Li Ling L Yuan Lamei L Zheng Wen W Yang Yan Y Deng Xiong X Song Zhi Z Deng Hao H

Frontiers in neurology 20230727

Genetic epilepsy with febrile seizures plus (GEFSP) is a familial epileptic syndrome that is genetically heterogeneous and inherited in an autosomal dominant form in most cases. To date, at least seven genes have been reported to associate with GEFSP. This study aimed to identify the disease-causing variant in a Chinese Tujia ethnic family with GEFSP by using whole exome sequencing, Sanger sequencing, and <i>in silico</i> prediction. A heterozygous missense variant c.5725A>G (p.T1909A) was ident ...[more]

PMID: 37576022

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Project description:PurposeMutations in the voltage-gated sodium channel (VGSC) gene SCN1A are responsible for a number of epilepsy disorders, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. In addition to seizures, patients with SCN1A mutations often experience sleep abnormalities, suggesting that SCN1A may also play a role in the neuronal pathways involved in the regulation of sleep. However, to date, a role for SCN1A in the regulation of sleep architecture has not been directly examined. To fill this gap, we tested the hypothesis that SCN1A contributes to the regulation of sleep architecture, and by extension, that SCN1A dysfunction contributes to the sleep abnormalities observed in patients with SCN1A mutations.MethodsUsing immunohistochemistry we first examined the expression of mouse Scn1a in regions of the mouse brain that are known to be involved in seizure generation and sleep regulation. Next, we performed detailed analysis of sleep and wake electroencephalography (EEG) patterns during 48 continuous hours of baseline recordings in a knock-in mouse line that expresses the human SCN1A GEFS+ mutation R1648H (RH mutants). We also characterized the sleep-wake pattern following 6 h of sleep deprivation.Key findingsImmunohistochemistry revealed broad expression of Scn1a in the neocortex, hippocampus, hypothalamus, thalamic reticular nuclei, dorsal raphe nuclei, pedunculopontine, and laterodorsal tegmental nuclei. Co-localization between Scn1a immunoreactivity and critical cell types within these regions was also observed. EEG analysis under baseline conditions revealed increased wakefulness and reduced non-rapid eye movement (NREM) and rapid eye movement (REM) sleep amounts during the dark phase in the RH mutants, suggesting a sleep deficit. Nevertheless, the mutants exhibited levels of NREM and REM sleep that were generally similar to wild-type littermates during the recovery period following 6 h of sleep deprivation.SignificanceThese results establish a direct role for SCN1A in the regulation of sleep and suggest that patients with SCN1A mutations may experience chronic alterations in sleep, potentially leading to negative outcomes over time. In addition, the expression of Scn1a in specific cell types/brain regions that are known to play critical roles in seizure generation and sleep now provides a mechanistic basis for the clinical features (seizures and sleep abnormalities) associated with human SCN1A mutations.

Project description:Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.

Dataset Information

An SCN1A gene missense variant in a Chinese Tujia ethnic family with genetic epilepsy with febrile seizures plus.

Publications

An <i>SCN1A</i> gene missense variant in a Chinese Tujia ethnic family with genetic epilepsy with febrile seizures plus.

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