Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10−15; Cleveland: P = 2.85×10−4; Finnish-ancestry Epi25: P = 1.80×10−4) or population controls (Epi25: P = 2.35×10−70; Cleveland: P = 1.43×10−7; Finnish-ancestry Epi25: P = 3.11×10−4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10−4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10−19; Cleveland: P = 1.69×10−6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10−15; Cleveland: P = 1.39×10−2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls—in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.

Objective: To identify cognitive phenotypes in temporal lobe epilepsy (TLE) and test their reproducibility in a large, multi-site cohort of patients using both datadriven and clinically driven approaches. Method: Four-hundred seven patients with TLE who underwent a comprehensive neuropsychological evaluation at one of four epilepsy centers were included. Scores on tests of verbal memory, naming, fluency, executive function, and psychomotor speed were converted into z-scores based on 151 healthy controls (HCs). For the data-driven method, cluster analysis (k-means) was used to determine the optimal number of clusters. For the clinically driven method, impairment was defined as

Purpose To characterize cognition in individuals with germline PTEN mutations (N=23) as well as in PTEN mutation-negative individuals with classic Cowden Syndrome or Bannayan-Riley-Ruvalcaba Syndrome (N=2). Methods Twenty-five individuals completed a comprehensive neuropsychological evaluation. One sample t-tests and effect sizes were used to examine differences in participant test scores compared with normal controls. Composite scores were created for each patient within each of the cognitive domains assessed and classified as above average, average, or below average according to normative standards. Chi-square analyses compared these classifications to expected proportions in normal control samples. Results The mean IQ was in the average range, and there was a wide range of intellectual functioning (extremely low to very superior). However, scores were lower than expected on measures of motor functioning, executive functioning, and memory recall suggesting a pattern of frontal lobe dysfunction in a large subset of participants. Conclusion This is the first study to characterize cognition in individuals with PTEN mutations and associated syndromes using a comprehensive neuropsychological battery. Contrary to previous association with intellectual disability, mean IQ was average, and there was a broad range of intellectual abilities. Specific evidence of frontal lobe dysfunction may have implications for treatment compliance and cancer surveillance and warrants further investigation.

In addition to discussions regarding risk for memory decline following left TLR, patients should be counseled about potential decline in word-finding ability.