Diagnostic implications of genetic copy number variation in epilepsy plus

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EuroEPINOMICS- RES Consortium , EpiCNV Consortium , Coppola , A , Cellini , E , Saarentaus , E , Palotie , A , Lehesjioki , A-E & von Spiczak , S 2019 , ' Diagnostic implications of genetic copy number variation in epilepsy plus ' , Epilepsia , vol. 60 , no. 4 , pp. 689-706 . https://doi.org/10.1111/epi.14683

Title: Diagnostic implications of genetic copy number variation in epilepsy plus
Author: EuroEPINOMICS- RES Consortium; EpiCNV Consortium; Coppola, Antonietta; Cellini, Elena; Saarentaus, Elmo; Palotie, Aarno; Lehesjioki, Anna-Elina; von Spiczak, Sarah
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Department of Medical and Clinical Genetics
Date: 2019-04
Language: eng
Number of pages: 18
Belongs to series: Epilepsia
ISSN: 0013-9580
URI: http://hdl.handle.net/10138/301411
Abstract: Objective Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available. Methods We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had "epilepsy plus," defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51-6.68; P = 2.34 x 10(-9)). Meta-analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. Significance The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large-scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.
Subject: array CGH
copy number variants
epilepsy genes
SNP array
3112 Neurosciences
3124 Neurology and psychiatry
1184 Genetics, developmental biology, physiology

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