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We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug\u2010resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippocampal sclerosis and\u2009\u22652\u2010year postsurgical follow\u2010up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Nine centers from 3 continents contributed 206 patients operated for drug\u2010resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss\u2010of\u2010function (LoF) variants (odds ratio [OR]\u00a0=\u00a02.6, 95% confidence interval [CI]\u00a0=\u00a01.9\u20133.5, <jats:italic>p<\/jats:italic>\u00a0=\u20091.3E\u201009) and in genes encoding voltage\u2010gated cation channels (OR\u00a0=\u00a02.4, 95% CI\u00a0=\u00a01.4\u20133.8, <jats:italic>p<\/jats:italic>\u00a0=\u20092.7E\u201004). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between\u2010group differences.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision\u2010making and counseling. 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