Technological and computational approaches to detect somatic mosaicism in epilepsy

Christian M Boßelmann; Costin Leu; Dennis Lal

doi:10.1016/j.nbd.2023.106208

Technological and computational approaches to detect somatic mosaicism in epilepsy

Neurobiol Dis. 2023 Aug:184:106208. doi: 10.1016/j.nbd.2023.106208. Epub 2023 Jun 19.

Authors

Christian M Boßelmann¹, Costin Leu², Dennis Lal³

Affiliations

¹ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
² Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK. Electronic address: [email protected].
³ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T., Cambridge, MA, USA; Cologne Center for Genomics (CCG), University of Cologne, Cologne, DE, USA.

PMID: 37343892
DOI: 10.1016/j.nbd.2023.106208

Abstract

Lesional epilepsy is a common and severe disease commonly associated with malformations of cortical development, including focal cortical dysplasia and hemimegalencephaly. Recent advances in sequencing and variant calling technologies have identified several genetic causes, including both short/single nucleotide and structural somatic variation. In this review, we aim to provide a comprehensive overview of the methodological advancements in this field while highlighting the unresolved technological and computational challenges that persist, including ultra-low variant allele fractions in bulk tissue, low availability of paired control samples, spatial variability of mutational burden within the lesion, and the issue of false-positive calls and validation procedures. Information from genetic testing in focal epilepsy may be integrated into clinical care to inform histopathological diagnosis, postoperative prognosis, and candidate precision therapies.

Keywords: Epilepsy; Focal cortical dysplasia; Genetics; Hemimegalencephaly; Somatic variant.

Publication types

Review

MeSH terms

Brain / pathology
Epilepsy* / genetics
Epilepsy* / pathology
Hemimegalencephaly* / genetics
Hemimegalencephaly* / pathology
Humans
Malformations of Cortical Development* / genetics
Mosaicism
Mutation