Diagnostic yield of chromosomal microarray and virtual targeted gene panel analysis in adults with focal epilepsy:...

The genetic basis of focal epilepsies is increasingly recognised, yet remains underappreciated in adults. We aimed to assess the diagnostic yield of genetic testing in adults with focal epilepsy and evaluate the optimal testing strategy.

We conducted a retrospective observational study of consecutive adult individuals with focal epilepsy evaluated for a genetic cause at our centre between 2021 and 2023. Chromosomal microarray analysis (CMA), the first-tier test in our algorithm, was performed in all cases. In a subset of CMA-negative individuals, exome sequencing with a virtual targeted gene panel (ES-TGP) was subsequently carried out. Demographic, clinical, and genetic data were reviewed.

Ninety-nine individuals were included. CMA identified pathogenic copy number variants (CNVs) in 7 cases (7.1 %). ES-TGP, performed in 69 individuals, detected pathogenic or likely pathogenic variants in 11 (15.9 %). Neurodevelopmental disorders (NDD) and malformations of cortical development (MCD) were significantly associated with positive findings on CMA and ES-TGP, respectively.

Genetic testing provides meaningful diagnostic value in adults with focal epilepsy. Testing strategies should consider both patient phenotype and local healthcare system resources. While CMA remains a useful initial tool in settings with limited access to next-generation sequencing (NGS)-base techniques, particularly for individuals with NDD, the higher yield of ES-TGP supports prioritising NGS, especially in individuals with MCD or after negative CMA. Relying solely on CMA may delay or prevent a definitive genetic diagnosis. The lower ES-TGP yield compared to paediatric cohorts likely reflects challenges in segregation analysis in adults. Further data from well-characterised adult cohorts are warranted to refine testing algorithms.