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The phenotypic spectrum associated with loss-of-function variants in monogenic epilepsy genes in the general population


Variants in monogenic epilepsy genes can cause phenotypes of varying severity. For example, pathogenic variants in the SCN1A gene can cause the severe, sporadic, and drug-resistant Dravet syndrome or the milder familiar GEFS + syndrome. We hypothesized that coding variants in epilepsy-associated genes could lead to other disease-related phenotypes in the general population. We selected 127 established monogenic epilepsy genes and explored rare loss-of-function (LoF) variant associations with 3700 phenotypes across 281,850 individuals from the UK Biobank with whole-exome sequencing data. For 5.5% of epilepsy genes, we found significant associations of LoF variants with non-epilepsy phenotypes, mostly related to mental health. These findings suggest that LoF variants in epilepsy genes are associated with neurological or psychiatric phenotypes in the general population. The evidence provided may warrant further research and genetic screening of patients with atypical presentation and inform clinical care of comorbid disorders in individuals with monogenic epilepsy forms.

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Fig. 1: Significant genotype-phenotype associations in epilepsy-associated genes.

Data availability

The data analyzed during this study can be found on GeneBass ( [9].


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This research has been conducted using summary statistics generated from the UK Biobank resource (under application 26041 and 48511).


This research did not receive any grant from the public, commercial, or not-for-profit funding agencies.

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Authors and Affiliations



CL and DL designed the study. VS analyzed the data. VS, JALR, CL, and DL wrote the paper. CL and DL supervised the study. All authors interpreted the data and revised the paper.

Corresponding author

Correspondence to Dennis Lal.

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The authors declare no competing interests.

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No ethical approval was required. The study used de-identified gene-based association summary statistics.

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Supplementary information

Table S1: Established epilepsy genes from three studies

Table S2: Detailed descriptions of the GeneBass phenotypes


Table S3: Loss-of-functon(LoF) variants with single-variant P-value <0.05 in the genes with significant genotype-phenotype associations.

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Smuk, V., López-Rivera, J.A., Leu, C. et al. The phenotypic spectrum associated with loss-of-function variants in monogenic epilepsy genes in the general population. Eur J Hum Genet 31, 243–247 (2023).

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