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Review
. 2023 Apr 1;36(2):86-94.
doi: 10.1097/WCO.0000000000001141. Epub 2023 Feb 10.

The current landscape of epilepsy genetics: where are we, and where are we going?

Sarah M Ruggiero  1   2   3 , Julie Xian  1   2   3 , Ingo Helbig  1   2   3   4
Affiliations
Review

The current landscape of epilepsy genetics: where are we, and where are we going?

Sarah M Ruggiero et al. Curr Opin Neurol. .

Abstract

Purpose of review: In this review, we aim to analyse the progress in understanding the genetic basis of the epilepsies, as well as ongoing efforts to define the increasingly diverse and novel presentations, phenotypes and divergences from the expected that have continually characterized the field.

Recent findings: A genetic workup is now considered to be standard of care for individuals with an unexplained epilepsy, due to mounting evidence that genetic diagnoses significantly influence treatment choices, prognostication, community support, and increasingly, access to clinical trials. As more individuals with epilepsy are tested, novel presentations of known epilepsy genes are being discovered, and more individuals with self-limited epilepsy are able to attain genetic diagnoses. In addition, new genes causative of epilepsy are being uncovered through both traditional and novel methods, including large international data-sharing collaborations and massive sequencing efforts as well as computational methods and analyses driven by the Human Phenotype Ontology (HPO).

Summary: New approaches to gene discovery and characterization are advancing rapidly our understanding of the genetic and phenotypic architecture of the epilepsies. This review highlights relevant and groundbreaking studies published recently that have pushed forward the field of epilepsy genetics.

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Conflict of interest statement

CONFLICTS OF INTEREST

None of the authors have any conflicts of interest to declare.

Figures

Figure 1.
Figure 1.. A recent history of gene identification and phenotypic characterizations of the epilepsies.
A. The pace of gene discovery is continuing at a steady pace but slowing over time as we reach the limits of gene discovery power achievable with current exome studies. However, our knowledge of phenotypic characterization continues to rapidly increase, leveraged by large studies of many hundreds of individuals with genetic epilepsy. B. Evidence supporting the validity of gene-disease relationship is bolstered over time by repeated case series, natural history analyses, and evidence gained from functional testing. Importantly, mounting genetic and experimental evidence also leads to gene-disease relationships being refuted over time (as represented by genes highlighted in red).
Figure 2.
Figure 2.. Novel methods of phenotypic characterization.
A. Representation of the Human Phenotype Ontology (HPO), the system that has accelerated phenotypic characterization through computational methods. Example HPO terms with their associated standardized code are shown. B. Genotype/ phenotype correlations that emerge for STXBP1 related disorders when approached through methods of phenotype reconstruction (from Xian et al., 2021-open access paper). Red points indicated HPO terms with uncorrected P-values < 0.05, while blue points indicated HPO terms with uncorrected P-values ≥ 0.05 C. Longitudinal seizure reconstruction of three of the most common causes of genetic epilepsy, demonstrating the difference in seizure presentation in the first three years of life, which can be reconstructed from data already within the Electronic Medical Record (EMR).
See this image and copyright information in PMC

References

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      **This practice guideline provides the first evidence-based approach to genetic testing and counseling for individuals with unexplained epilepsy

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