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

Authors

Breana Galea, Joshua Reid, Samuel Gooley, Tom Witkowski, Tara Lane, Sian Macdonald, Timothy E Green, Zimeng Ye, Thiuni Adikari, Kristian Bulluss, Saul A Mullen, Caitlin A Bennett, Brialie Forster, Gabi Bradshaw, Wendi Lin, Wasanthi De Silva, Rosita B Ramirez, Sattar Khoshkhoo, Sachin Gupta, Michael Krivanek, Kavitha Kothur, Deepak Gill, Kate Pope, Greta Gillies, Matthew Coleman, Wei-Shern Lee, Sarah M Stephenson, Wirginia Maixner, A Simon Harvey, Emma Macdonald-Laurs, Katherine B Howell, Colleen D'Arcy, Paul J Lockhart, Richard J Leventer, Renata M Kalnins, Jonathan Clark, Mark F Bennett, Melanie Bahlo, Ingrid E Scheffer, Piero Perucca, Samuel F Berkovic, Michael S Hildebrand

Published in

Progress in neuro-psychopharmacology & biological psychiatry. Pages 111920. Sep 06, 2026. Epub Sep 06, 2026.

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, 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.

PMID:
42702231
Bibliographic data and abstract were imported from PubMed on 07 Sep 2026.

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