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Over the past decade, there has been tremendous progress in understanding brain somatic mosaicism in epilepsy in the research setting. Access to resected brain tissue samples from patients with medically refractory epilepsy undergoing epilepsy surgery has been key to making these discoveries. In this review, we discuss the gap between making discoveries in the research setting and bringing results back to the clinical setting. Current clinical genetic testing mainly uses clinically accessible tissue samples, like blood and saliva, and can detect inherited and de novo germline variants and potentially non-brain-limited mosaic variants that have resulted from post-zygotic mutation (also called “somatic mutations”). Methods developed in the research setting to detect brain-limited mosaic variants using brain tissue samples need to be further translated and validated in the clinical setting, which will allow post-resection brain tissue genetic diagnoses. However, obtaining a genetic diagnosis after surgery for refractory focal epilepsy, when brain tissue samples are available, is arguably “too late” to guide precision management. Emerging methods using cerebrospinal fluid (CSF) and stereoelectroencephalography (SEEG) electrodes hold promise for establishing genetic diagnoses pre-resection without the need for actual brain tissue. In parallel, development of curation rules for interpreting the pathogenicity of mosaic variants, which have unique considerations compared to germline variants, will assist clinically accredited laboratories and epilepsy geneticists in making genetic diagnoses. Returning results of brain-limited mosaic variants to patients and their families will end their diagnostic odyssey and advance epilepsy precision management. |
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