Evidence map›Paper›PMID 42702231›Full record

ArticleProgress in neuro-psychopharmacology & biological psychiatry2026

Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia.

Breana Galea, Joshua Reid, Samuel Gooley, Tom Witkowski, Tara Lane, Sian Macdonald, Timothy E Green, Zimeng Ye, Thiuni Adikari, Kristian Bulluss and 32 more

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Article in Progress in neuro-psychopharmacology & biological psychiatry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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42 authors.

Breana GaleaEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia.
Joshua ReidEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia; Genetics and Gene Regulation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3052, Australia.
Samuel GooleyEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
Tom WitkowskiEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
Tara LaneEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Sian MacdonaldEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
Timothy E GreenEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Zimeng YeEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
Thiuni AdikariEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
Kristian BullussDepartment of Neurosurgery, Austin Health, Heidelberg, Victoria 3084, Australia.
Saul A MullenEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
Caitlin A BennettEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
Brialie ForsterEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
Gabi BradshawMolecular Pathology, Austin Health, Heidelberg, Victoria 3084, Australia.
Wendi LinMolecular Pathology, Austin Health, Heidelberg, Victoria 3084, Australia.
Wasanthi De SilvaMolecular Pathology, Austin Health, Heidelberg, Victoria 3084, Australia.
Rosita B RamirezDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Sattar KhoshkhooDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston, MA 02115, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Sachin GuptaTY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, New South Wales 2145, Australia.
Michael KrivanekDepartment of Histopathology, The Children's Hospital at Westmead, Sydney, New South Wales 2145, Australia.
Kavitha KothurTY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, New South Wales 2145, Australia; University of Sydney, The Children's Hospital at Westmead, Sydney, New South Wales 2145, Australia; Kids Neuroscience Centre, The Children's Hospital at Westmead, Sydney, New South Wales 2145, Australia.
Deepak GillTY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, New South Wales 2145, Australia; University of Sydney, The Children's Hospital at Westmead, Sydney, New South Wales 2145, Australia; Kids Neuroscience Centre, The Children's Hospital at Westmead, Sydney, New South Wales 2145, Australia.
Kate PopeMurdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Greta GilliesMurdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Matthew ColemanMurdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia; Department of Paediatrics, The University of Melbourne, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Wei-Shern LeeMurdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia; Department of Paediatrics, The University of Melbourne, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Sarah M StephensonMurdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia; Department of Paediatrics, The University of Melbourne, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Wirginia MaixnerDepartment of Neurosurgery, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
A Simon HarveyFlorey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia; Department of Paediatrics, The University of Melbourne, The Royal Children's Hospital, Parkville, Victoria 3052, Australia; Department of Neurology, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Emma Macdonald-LaursFlorey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia; Department of Paediatrics, The University of Melbourne, The Royal Children's Hospital, Parkville, Victoria 3052, Australia; Department of Neurology, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Katherine B HowellMurdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia; Department of Neurology, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Colleen D'ArcyDepartment of Anatomical Pathology, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Paul J LockhartMurdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia; Department of Paediatrics, The University of Melbourne, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Richard J LeventerMurdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia; Department of Neurology, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Renata M KalninsAnatomical Pathology, Austin Health, Heidelberg, Victoria 3084, Australia.
Jonathan ClarkAnatomical Pathology, Austin Health, Heidelberg, Victoria 3084, Australia.
Mark F BennettEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia; Genetics and Gene Regulation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3052, Australia.
Melanie BahloGenetics and Gene Regulation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3052, Australia.
Ingrid E SchefferEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia; Genetics and Gene Regulation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Paediatrics, The University of Melbourne, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Piero PeruccaEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
Samuel F BerkovicEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
Michael S HildebrandEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia. Electronic address: michael.hildebrand@unimelb.edu.au.

Funding

Genetic and Cellular Mechanisms of Temporal Lobe EpilepsyK08NS128272 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI Sattar Khoshkhoo · 2022 to 2026
$1.2M
NINDS NIH HHS K08 NS128272
6 · The paper itself

Abstract

Focal cortical dysplasias (FCDs) are malformations of cortical development associated with drug-resistant focal epilepsy. We analyzed surgical tissue from 25 consecutive cases recruited from adult and pediatric epilepsy surgery programs. We performed high-depth sequencing of lesional tissue, validated somatic variants using droplet digital PCR or amplicon sequencing, and investigated genotype-phenotype correlations. A pathogenic or likely pathogenic variant was detected in 64% (n = 16/25) of cases. Of these, five cases with FCDIIa or FCDIIb had germline variants in NPRL3 (n = 3) or DEPDC5 (n = 2). Somatic variants were identified in 44% (n = 11/25) of cases. The genetic yield for FCDIIb was 77% of cases having a pathogenic mTOR pathway variant detected (n = 10/13), and for FCDIIa 66% (n = 6/9). High depth sequencing approaches allowed detection of somatic variants with very low (down to 0.4%) variant allele fractions (VAFs). No pathogenic variants were detected in 3 cases with FCDI. 62% (n = 15/24) of the cases with ≥12 months follow up experienced a favourable seizure outcome (Engel 1-2) following surgery. Of note, n = 9 patients required repeat surgery to resect residual dysplasia. Determining a genetic diagnosis reveals aetiology and paves the way to precision therapies that may benefit those with FCD who do not respond to current treatments.

Indexed as

Drug Resistant EpilepsyFocal Cortical DysplasiaHigh-Throughput Nucleotide SequencingMalformations of Cortical DevelopmentAdolescentAdultChildChild, PreschoolFemaleGenetic Association StudiesGTPase-Activating ProteinsHumansMaleYoung AdultDEPDC5 protein, humanGTPase-Activating ProteinsDysplasiaEpilepsyEpilepsy surgeryLesionMosaicismSequencing

Identifiers

PMID42702231
PMCPMC13653638

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