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

European Journal of Human Genetics volume 31, pages 243–247 (2023)Cite this article

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Abstract

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 (https://genebass.org/) [9].

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Acknowledgements

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

Funding

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

Author information

Authors and Affiliations

  1. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Victoria Smuk, Javier A. López-Rivera, Costin Leu & Dennis Lal

  2. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Javier A. López-Rivera

  3. Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK

    Costin Leu

  4. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Costin Leu & Dennis Lal

  5. Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

    Dennis Lal

  6. Cologne Center for Genomics, University of Cologne, Cologne, NRW, Germany

    Dennis Lal

Authors
  1. Victoria Smuk
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  2. Javier A. López-Rivera
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  3. Costin Leu
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  4. Dennis Lal
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Contributions

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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Competing interests

The authors declare no competing interests.

Ethics approval

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

41431_2022_1211_MOESM3_ESM.xlsx

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). https://doi.org/10.1038/s41431-022-01211-w

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