Cutting edge approaches to detecting brain mosaicism associated with common focal epilepsies: implications for diagnosis and potential therapies

ABSTRACT

Introduction

Mosaic variants arising in brain tissue are increasingly being recognized as a hidden cause of focal epilepsy. This knowledge gain has been driven by new, highly sensitive genetic technologies and genome-wide analysis of brain tissue from surgical resection or autopsy in a small proportion of patients with focal epilepsy. Recently reported novel strategies to detect mosaic variants limited to brain have exploited trace brain DNA obtained from cerebrospinal fluid liquid biopsies or stereo-electroencephalography electrodes.

Areas covered

The authors review the data on these innovative approaches published in PubMed before 12 June 2021, discuss the challenges associated with their application, and describe how they are likely to improve detection of mosaic variants to provide new molecular diagnoses and therapeutic targets for focal epilepsy, with potential utility in other nonmalignant neurological disorders.

Expert opinion

These cutting-edge approaches may reveal the hidden genetic etiology of focal epilepsies and provide guidance for precision medicine.

KEYWORDS:

• Brain lesion
• CSF liquid biopsy
• high-depth exome sequencing
• focal epilepsy
• stereo-electroencephalography
• somatic mosaicism

Article highlights

• Mosaicism is increasingly being recognized as an important cause of focal epilepsy

• Current routes to detect mosaicism are via privileged access to brain tissue from surgical resection or autopsy

• Alternative approaches are needed to identify mosaic pathogenic variants in brain when tissue is not clinically accessible

• Cerebrospinal fluid or stereo-electroencephalography electrodes provide novel approaches to detect somatic mosaicism in brain

• These techniques may reveal the hidden genetic etiology of the largest group of epilepsies, the focal epilepsies, with the hope of identifying new therapeutic targets

Declaration of interests

IE Scheffer has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, BioMarin, Nutricia, Rogcon, Chiesi, Encoded Therapeutics, Knopp Biosciences and Xenon Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, Liva Nova, and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, BioMarin, and Eisai; has served as an investigator for Zogenix, Zynerba, Ultragenyx, GW Pharma, UCB, Eisai, Xenon Pharmaceuticals, Anavex Life Sciences, Ovid Therapeutics, Epigenyx, Encoded Therapeutics, and Marinus; and has consulted for Zynerba Pharmaceuticals, Atheneum Partners, Ovid Therapeutics, Care Beyond Diagnosis, Epilepsy Consortium, and UCB. She may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics Inc and licensed to various diagnostic companies; has a patent molecular diagnostic/theranostic target for benign familial infantile epilepsy (BFIE) [PRRT2] 2011904493 & 2,012900190 and PCT/AU2012/001321 (TECH ID:2012–009). PP has received speaker honoraria or consultancy fees for his institution from Chiesi, Eisai, LivaNova, Novartis, Sun Pharma, Supernus, and UCB Pharma, outside the submitted work. He is an Associate Editor for Epilepsia Open. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

MF Bennett was supported by a Taking Flight Award from CURE Epilepsy. M Bahlo was supported by an NHMRC Investigator Grant (1195236). IES was supported by a NHMRC Investigator Grant and MRFF grant. P Perucca is supported by the National Health and Medical Research Council (APP1163708), the Epilepsy Foundation, The University of Melbourne, Monash University, Brain Australia, and the Weary Dunlop Medical Research Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was funded by the National Health and Medical Research Council Australia, the Australian Epilepsy Research Foundation, and Sir Weary Dunlop Medical Research Foundation. This work was also made possible through the Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council (NHMRC) Independent Research Institute Infrastructure Support Scheme (IRIISS).