Background Genetic epilepsy with febrile seizures plus (GEFS+), an inherited epilepsy syndrome, is characterized by broad genotypic and phenotypic heterogeneity, with causative genes remaining unidentified in approximately 70% of cases.. The aim of this study was to explore the clinical and genetic profile of GEFS+ . Method We retrospectively analyzed the genotypic spectrum and clinical characteristics of 133 GEFS+ families. Probands were divided into two groups based on their degree of fever sensitivity to compare the phenotypic and genetic differences. A PPI analysis was conducted to declare the interaction of involved genes. Results 392 affected patients were identified from 133 GEFS+ families. FS (288/392, 58.2%) and FS+ (70/392, 17.9%) consisted of the majority of phenotypes. Other phenotypes included FS/FS+ with generalized seizures (21/392, 5.4%), FS/FS+ with focal seizures (8/392, 2.0%), Dravet syndrome (8/392, 2.0%), afebrile GTCS (17/392, 4.3%), complex phenotypes (5/392, 1.3%) and unclassified seizures (35/392, 8.9%). Patients who were mildly sensitive to fever were more likely to have focal, myoclonic, and tonic seizures, and have two or more seizure types, whereas patients being highly sensitive to fever were more inclined to have only one type of seizures (P < 0.05). Meanwhile, patients being mildly sensitive to fever have more probability to require antiseizure medications (P < 0.05). WES or WGS was undertaken in 127 families. 83 variants of 43 different genes (31 P/LP variants and 52 VUS variants) were identified in 78 GEFS+ families, with a diagnostic yield of 23.6%. The most commonly implicated genes were predominantly voltage-gated channels genes (SCN1A, SCN1B, KCNT1, CACNA1A, CACNA1H), and GABA receptor-related genes (GABRA1, GABRB2, GABRB3, GABRG2). Venn diagram analysis showed that voltage-gated channel genes distributed across different fever-sensitivity groups, while GABA receptor-related genes were more frequently in high- and moderate-sensitivity groups. Conclusion The phenotypic spectrum of GEFS+ was broad and FS and FS+ constituted the main phenotypes. Multiple types of seizures and intellectual disability/developmental delay (ID/DD) were more likely to occur in children with low fever sensitivity. Sodium voltage-gated channel genes, especially SCN1A, and GABA receptor-related genes were frequent in the genotypic spectrum of GEFS+. GABA receptor-related genes, but not voltage-gated channel genes, were closely related to fever-sensitivity.

Clinical and genetics spectrum of 392 Chinese patients with genetic epilepsy with febrile seizures plus

期刊论文
发表日期：

2025年12月10日

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Shimeng Chen,
Yulin Quan,
Fei Yin,
Jing Peng

摘要

Background

Genetic epilepsy with febrile seizures plus (GEFS+), an inherited epilepsy syndrome, is characterized by broad genotypic and phenotypic heterogeneity, with causative genes remaining unidentified in approximately 70% of cases.. The aim of this study was to explore the clinical and genetic profile of GEFS+ .

Method

We retrospectively analyzed the genotypic spectrum and clinical characteristics of 133 GEFS+ families. Probands were divided into two groups based on their degree of fever sensitivity to compare the phenotypic and genetic differences. A PPI analysis was conducted to declare the interaction of involved genes.

Results

392 affected patients were identified from 133 GEFS+ families. FS (288/392, 58.2%) and FS+ (70/392, 17.9%) consisted of the majority of phenotypes. Other phenotypes included FS/FS+ with generalized seizures (21/392, 5.4%), FS/FS+ with focal seizures (8/392, 2.0%), Dravet syndrome (8/392, 2.0%), afebrile GTCS (17/392, 4.3%), complex phenotypes (5/392, 1.3%) and unclassified seizures (35/392, 8.9%). Patients who were mildly sensitive to fever were more likely to have focal, myoclonic, and tonic seizures, and have two or more seizure types, whereas patients being highly sensitive to fever were more inclined to have only one type of seizures (P < 0.05). Meanwhile, patients being mildly sensitive to fever have more probability to require antiseizure medications (P < 0.05). WES or WGS was undertaken in 127 families. 83 variants of 43 different genes (31 P/LP variants and 52 VUS variants) were identified in 78 GEFS+ families, with a diagnostic yield of 23.6%. The most commonly implicated genes were predominantly voltage-gated channels genes (SCN1A, SCN1B, KCNT1, CACNA1A, CACNA1H), and GABA receptor-related genes (GABRA1, GABRB2, GABRB3, GABRG2). Venn diagram analysis showed that voltage-gated channel genes distributed across different fever-sensitivity groups, while GABA receptor-related genes were more frequently in high- and moderate-sensitivity groups.

Conclusion

The phenotypic spectrum of GEFS+ was broad and FS and FS+ constituted the main phenotypes. Multiple types of seizures and intellectual disability/developmental delay (ID/DD) were more likely to occur in children with low fever sensitivity. Sodium voltage-gated channel genes, especially SCN1A, and GABA receptor-related genes were frequent in the genotypic spectrum of GEFS+. GABA receptor-related genes, but not voltage-gated channel genes, were closely related to fever-sensitivity.