Citation for final published version:Thomas, Rhys 2017. Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. Please note: Changes made as a result of publishing processes such as copy-editing, formatting and page numbers may not be reflected in this version. For the definitive version of this publication, please refer to the published source. You are advised to consult the publisher's version if you wish to cite this paper.This version is being made available in accordance with publisher policies. See http://orca.cf.ac.uk/policies.html for usage policies. Copyright and moral rights for publications made available in ORCA are retained by the copyright holders.

Pure PNES patients showed similarities and differences in the psychiatric profile, with a greater prevalence of dissociative disorders and PTSD, factors related to psychiatric severity.

Summary:Purpose: To determine the predictive value of clinical features and medical history in patients with nonepileptic seizures (NESs).Methods: One hundred sixty-one consecutive ictal videoEEGs were reviewed, and 17 patients with 41 NESs identified. NES diagnosis was defined as paroxysmal behavioral changes suggestive of epileptic seizures recorded during video-EEG without any electrographic ictal activity. Clinical features, age, sex, coexisting epilepsy, associated psychiatric disorder, social and economic factors, delay in reaching the diagnosis of NES, previous treatment, and correlation with outcome on follow-up were examined.Results: The study population included 70% female patients with a mean age of 33 years. Mean duration of NESs before diagnosis was 9 years. Forty-one percent had coexisting epilepsy. The most frequent NES clinical features were tonicclonic mimicking movements and fear/anxiety/hyperventilation. The most common psychiatric diagnosis was conversion disorder and dependent and borderline personality disorder. Seventy-three percent of patients with pure NESs received antiepileptic drugs (AEDs), and 63.5% of this group received new AEDs. Fifty-nine percent of the patients received psychological/psychiatric therapy. At follow-up, 23.5% were free of NESs.Conclusions: All seizure-free patients had two good prognostic factors: having an independent lifestyle and the acceptance of the nonepileptic nature of the episodes. Video-EEG monitoring continues to be the diagnostic method to ensure accurate seizure classification. Establishing adequate health care programs to facilitate access to new technology in public hospitals as well as the implementation of continuous education programs for general practitioners and neurologists could eventually improve the diagnosis and treatment of patients with NESs.

In the list of consortium members for the Epilepsy Phenome/Genome Project, member Dina Amrom's name was misspelled as Amron. The authors regret the error.

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Previous studies have examined the association of a single nucleotide polymorphism at the promoter region of interleukin 1B (IL-1␤-511T) with temporal lobe epilepsy and febrile seizures susceptibility, but those studies have

Infantile spasms (IS) and Lennox Gastaut syndrome (LGS) are epileptic encephalopathies characterized by early-onset, intractable seizures and poor developmental outcomes. De novo sequence mutations and copy number variants (CNVs) are causative in a subset of cases. We used exome sequence data in 349 trios with IS or LGS to identify putative de novo CNVs. We confirm 18 de novo CNVs in 17 patients (4.8%), 10 of which are likely pathogenic, giving a firm genetic diagnosis for 2.9% of patients. Confirmation of exome-predicted CNVs by array-based methods is still required due to false positive rates of prediction algorithms. Our exome-based results are consistent with recent array-based studies in similar cohorts and highlight novel candidate genes for IS and LGS.

Neuronal migration disorders are a clinically and genetically heterogeneous group of malformations of cortical development, frequently responsible for severe disability. Despite the increasing knowledge of the molecular mechanisms underlying this group of diseases, their genetic diagnosis remains unattainable in a high proportion of cases. Here, we present the results of 38 patients with lissencephaly, periventricular heterotopia and subcortical band heterotopia from Argentina. We performed Sanger and Next Generation Sequencing (NGS) of DCX, FLNA and ARX and searched for copy number variations by MLPA in PAFAH1B1, DCX, POMT1, and POMGNT1. Additionally, somatic mosaicism at 5% or higher was investigated by means of targeted high coverage NGS of DCX, ARX, and PAFAH1B1. Our approach had a diagnostic yield of 36%. Pathogenic or likely pathogenic variants were identified in 14 patients, including 10 germline (five novel) and 4 somatic mutations in FLNA, DCX, ARX and PAFAH1B1 genes. This study represents the largest series of patients comprehensively characterized in our population. Our findings reinforce the importance of somatic mutations in the pathophysiology and diagnosis of neuronal migration disorders and contribute to expand their phenotype-genotype correlations.