Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy

MF Bennett; MS Hildebrand; S Kayumi; MA Corbett; S Gupta; Z Ye; M Krivanek; R Burgess; OJ Henry; JA Damiano; A Boys; J Gécz; M Bahlo; IE Scheffer; SF Berkovic

Journal article

Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy

MF Bennett, MS Hildebrand, S Kayumi, MA Corbett, S Gupta, Z Ye, M Krivanek, R Burgess, OJ Henry, JA Damiano, A Boys, J Gécz, M Bahlo, IE Scheffer, SF Berkovic

Neurology Genetics | Published : 2022

DOI: 10.1212/NXG.0000000000000652

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Abstract

Background and ObjectivesThe 2-hit model of genetic disease is well established in cancer, yet has only recently been reported to cause brain malformations associated with epilepsy. Pathogenic germline and somatic variants in genes in the mechanistic target of rapamycin (mTOR) pathway have been implicated in several malformations of cortical development. We investigated the 2-hit model by performing genetic analysis and searching for germline and somatic variants in genes in the mTOR and related pathways.MethodsWe searched for germline and somatic pathogenic variants in 2 brothers with drug-resistant focal epilepsy and surgically resected focal cortical dysplasia (FCD) type IIA. Exome sequen..

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University of Melbourne Researchers

Mark Bennett Author

Michael Hildebrand Author

Melanie Bahlo Author

Ingrid Scheffer Author

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Awarded by National Health and Medical Research Council

Funding Acknowledgements

This study was supported by National Health and Medical Research Council (NHMRC) funding: NHMRC Program Grants 1054618 and 1091593, NHMRC Project Grants 1079058 and 1129054, NHMRC Senior Research Fellowship 1102971, NHMRC Senior Practitioner Fellowship 1104831, NHMRC Senior Principal Research Fellowship 1155224, andNHMRC R. D. Wright Career Development Fellowship 1063799. This work was also supported by a CURE Epilepsy Taking Flight Award and through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institutes Infrastructure Support Scheme.