Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia
- Author(s)
- Galea, B; Reid, J; Gooley, S; Witkowski, T; Lane, T; Macdonald, S; Green, TE; Ye, Z; Adikari, T; Bulluss, K; Mullen, SA; Bennett, CA; Forster, B; Bradshaw, G; Lin, W; De Silva, W; Ramirez, RB; Khoshkhoo, S; Gupta, S; Krivanek, M; Kothur, K; Gill, D; Pope, K; Gillies, G; Coleman, M; Lee, WS; Stephenson, SM; Maixner, W; Harvey, AS; Macdonald-Laurs, E; Howell, KB; D'Arcy, C; Lockhart, PJ; Leventer, RJ; Kalnins, RM; Clark, J; Bennett, MF; Bahlo, M; Scheffer, IE; Perucca, P; Berkovic, SF; Hildebrand, MS;
- Journal Title
- Progress in Neuropsychopharmacology and Biological Psychiatry
- 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.
- Publisher
- Elsevier
- Keywords
- Dysplasia; Epilepsy; Epilepsy surgery; Lesion; Mosaicism; Sequencing
- Research Division(s)
- Genetics and Gene Regulation
- PubMed ID
- 42702231
- Publisher's Version
- https://doi.org/10.1016/j.pnpbp.2026.111920
- Open Access at Publisher's Site
https://doi.org/10.1016/j.pnpbp.2026.111920- Terms of Use/Rights Notice
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Creation Date: 2026-09-14 08:56:33
Last Modified: 2026-10-02 08:19:42