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Review
. 2020 Dec:65:1-7.
doi: 10.1016/j.gde.2020.04.004. Epub 2020 May 15.

Somatic variants in epilepsy - advancing gene discovery and disease mechanisms

Erin L Heinzen  1
Affiliations
Review

Somatic variants in epilepsy - advancing gene discovery and disease mechanisms

Erin L Heinzen. Curr Opin Genet Dev. 2020 Dec.

Abstract

In the past ten years, there has been increasing recognition that cells can acquire genetic variants during cortical development that can give rise to brain malformations as well as nonlesional focal epilepsy. These often brain tissue-specific, de novo variants can result in highly variable phenotypes based on the burden of a variant in specific tissues and cells. By discovering these variants, shared pathophysiological mechanisms are being revealed between clinically distinct disorders. Beyond informing disease mechanisms, mosaic variants also offer a powerful research tool to trace cellular lineages, to study the roles of specialized cell types in disease presentation, and to establish the cell-type specific genomic consequences of a variant.

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Conflict of interest statement

Competing Interests

The author declares no conflict of interest.

Figures

Figure 1.
Figure 1.
Additional complexities affecting the variable expressivity of genes harboring pathogenic post-zygotically acquired genetic variants.
Figure 2.
Figure 2.
Suggested model for SLC35A2 epilepsy whereby variant burden and localization dictate phenotypic severity. Figure made with Biorender.com
See this image and copyright information in PMC

References

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    1. Epi25 Collaborative: Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals. Am J Hum Genet 2019, 105:267–282. - PMC - PubMed

    1. EuroEPINOMICS-RES Consortium, Heyne HO, Singh T, Stamberger H, Jamra RA, Caglayan H, Craiu D,Jonghe PD,Guerrini R, Helbig KL, et al.: De novo variants in neurodevelopmental disorders with epilepsy. Nat Genet 2018, 50:1048–1053.

      * The Epi25 Collaborative reports the results of the largest exome sequencing study performed to date oncomparing 9,170 individuals with epilepsy, including individuals with developmental and epileptic encephalopathies, genetic generalized epilepsy, and nonacquired focal epilepsy, to ~8,500 controls. In all types of epilepsy there was an enrichment of ultra-rare deleterious variants in genes intolerant to functional variation suggesting that ultra-rare variants contribute to epilepsy risk. This study confirms the findings from an earlier study showing overlapping genetic contributors in both rare and common epilepsies.

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