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Publications

Journal Article Ahead of print

PubMed: 42847889 DOI: 10.1002/epi.70526

Deep whole genome sequencing of epileptogenic brain lesions.

Epilepsia

Authors: Christian M Boßelmann, Costin Leu, Lucas Hoffmann, Roland Coras, Katja Kobow, Hajo Hamer, Daniel Delev, Christian G Bien, Thilo Kalbhenn, Tom Pieper, Till Hartlieb, Kerstin Becker, Lisa Ferguson, Robyn M Busch, Peter Nürnberg, Imad Najm, Ingmar Blümcke, Dennis Lal

Affiliations

  • Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  • Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  • Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, partner of the European Reference Network EpiCARE, University of Tübingen, Tübingen, Germany.
  • Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA. Department of Neurology, University of Texas Health Science Center at Houston, Houston, Texas, USA. Center for Neurogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA.
  • Department of Neuropathology, partner of the European Reference Network EpiCARE, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • Epilepsy Center, partner of the European Reference Network EpiCARE, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • Department of Neurosurgery, partner of the European Reference Network EpiCARE, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • Department of Epileptology, Krankenhaus Mara, Bethel Epilepsy Center, Medical School OWL, Bielefeld University, Bielefeld, Germany.
  • Department of Neurosurgery (Evangelisches Klinikum Bethel), Medical School, Bielefeld University, Bielefeld, Germany.
  • Center for Pediatric Neurology, Neurorehabilitation, and Epileptology, Schoen-Clinic, Rosenheim, Germany.
  • Research Program for Rehabilitation, Transition, and Palliation, Paracelsus Medical University, Salzburg, Austria.
  • Cologne Center for Genomics, Medical Faculty, University of Cologne, Cologne, Germany.
  • Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
  • Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA. Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA. Department of Neurology, University of Texas Health Science Center at Houston, Houston, Texas, USA. Center for Neurogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA. Cologne Center for Genomics, Medical Faculty, University of Cologne, Cologne, Germany. Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. Center for Precision Health, Cook Children's Health Care System, Fort Worth, Texas, USA. Center for Innovation in Health Informatics, University of Texas at Arlington, Arlington, Texas, USA.

Abstract

OBJECTIVE

Malformations of cortical development and low-grade epilepsy-associated tumors often cause drug-resistant lesional focal epilepsy (LFE) amenable to surgical treatment. Genetic testing of resected brain tissue can provide diagnostic and mechanistic information and may eventually support personalized treatment approaches. However, systematic >300× whole genome sequencing (GS) of bulk epileptogenic lesions, particularly after nondiagnostic deep exome sequencing and array-based genotyping, has not been evaluated.

METHODS

Here, we performed deep GS (>300× coverage) on 33 epileptogenic brain lesions from individuals with LFE, selected for lesions with a high prior probability of a genetic finding, all of whom had negative results for candidate germline or somatic variants in previous deep exome sequencing (ES; >350× coverage) and array-based genotyping.

RESULTS

We identified candidate somatic variants in known LFE-associated genes in seven of 33 participants (21%). Two participants had two candidate variants each. In total, three of 33 participants (9%) had variants that could only be detected by GS: two deletions in TSC2, two deletions in NPRL3, and an exonic inversion in FGFR1. Three individuals had germline polymorphisms that may represent modulators or risk factors. Exploratory mutational signature analysis revealed clocklike signatures and a correlation between mutational signatures, age at seizure onset, and histopathology, indicating an age-related mechanism of mutation.

SIGNIFICANCE

Deep GS establishes the feasibility of genome-wide profiling at a depth relevant to low-variant allelic frequency mosaicism and reveals candidate variants missed by ES, particularly complex structural variants. As sequencing costs decrease, GS may complement other technologies in somatic variant detection, enabling more widespread clinical implementation of tissue sequencing in epilepsy surgery. Further studies are needed to address the remaining conceptual and technological challenges in somatic variant detection.

MeSH

Epilepsy, High-Throughput Nucleotide Sequencing, Whole Genome Sequencing, Brain, Genome, Exome, Therapeutics, Tissues, Wounds And Injuries, Mutation