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its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent d\u00e9j\u00e0 vu to a more severe phenotype with febrile seizures and hippocampal sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and\/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in individuals with FMTLE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We studied 134 families with \u2265\u20092 first or second\u2010degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one individual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The age of patients with FMTLE onset ranged from 2.5 to 70\u2009years (median\u2009=\u200918, interquartile range\u2009=\u200913\u201328\u2009years). The most common focal seizure symptom was d\u00e9j\u00e0 vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug\u2010resistance and\/or hippocampal sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio\u2009=\u20091.24, 95% confidence interval\u2009=\u20091.06, 1.46, <jats:italic>p<\/jats:italic>\u2009=\u20090.007); in contrast, no enrichment for the febrile seizure PRS was observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>FMTLE is a generally mild drug\u2010responsive syndrome with d\u00e9j\u00e0 vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub\u2010genome\u2010wide significant focal epilepsy genome\u2010wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023;94:825\u2013835<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26765","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T00:29:51Z","timestamp":1692664191000},"page":"825-835","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture"],"prefix":"10.1002","volume":"94","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2648-7828","authenticated-orcid":false,"given":"Rebekah V.","family":"Harris","sequence":"first","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine (Austin Health) The University of Melbourne  Heidelberg Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L.","family":"Oliver","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine (Austin Health) The 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