Diagnostic implications of genetic copy number variation in epilepsy plus

Coppola A1;2 3;Cellini E4;Stamberger H5;6 7;Saarentaus E8;9 10;11;Cetica V4;Lal D10;11 12;Djémié T5;6;Bartnik-Glaska M13;Ceulemans B14;Cross JH15;16 17;Deconinck T5;6;De Masi S7;Dorn T18;Guerrini R;Hoffman-Zacharska D14;Kooy F19;Lagae L20;Lench N21;Lemke JR22;Lucenteforte E23;24;Madia F25;Mefford HC26;Morrogh D21;Nuernberg P27;Palotie A11;13;Schoonjans AS15;Striano P28;Szczepanik E29;Tostevin A1;2;Vermeesch JR30;Van Esch H30;Van Paesschen W31;Waters JJ21;Weckhuysen S5;6 12;Zara F25;De Jonghe P5;6 12;Sisodiya SM1;2;Marini C;EuroEPINOMICS-RES Consortium;EpiCNV Consortium. Lehesjioki AE;Craiu D;Talvik T;Caglayan H;Serratosa J;Sterbova K;Møller RS;Hjalgrim H;Lerche H;Weber Y;Helbig I;von Spiczak S;Barba C;Bogaerts A;Boni A;Galizia EC;Chiari S;Di Gacomo G;Ferrari A;Garducci S;Giglio S

Member of the Collaboration Group

;Holmgren P;Leu C;Melani F;Novara F;Pantaleo M;Peeters E;Pisano T;Rosati A;Sander J;Schoeler N;Stankiewicz P;Striano S;Suls A;Traverso M;Vandeweyer G;Van Dijck A;Zuffardi O.

2019-01-01

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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 × 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.