Progress in neuro-psychopharmacology & biological psychiatry · 2026
Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia.
СтатьяНазвание и аннотация: Перевод в очереди
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Galea Breana, Reid Joshua, Gooley Samuel, Witkowski Tom, Lane Tara, Macdonald Sian, Green Timothy E, Ye Zimeng, Adikari Thiuni, Bulluss Kristian, Mullen Saul A, Bennett Caitlin A, Forster Brialie, Bradshaw Gabi, Lin Wendi, De Silva Wasanthi, Ramirez Rosita B, Khoshkhoo Sattar, Gupta Sachin, Krivanek Michael, Kothur Kavitha, Gill Deepak, Pope Kate, Gillies Greta, Coleman Matthew, Lee Wei-Shern, Stephenson Sarah M, Maixner Wirginia, Harvey A Simon, Macdonald-Laurs Emma, Howell Katherine B, D'Arcy Colleen, Lockhart Paul J, Leventer Richard J, Kalnins Renata M, Clark Jonathan, Bennett Mark F, Bahlo Melanie, Scheffer Ingrid E, Perucca Piero, Berkovic Samuel F, Hildebrand Michael S
Аннотация
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.