Diagnostic implications of genetic copy number variation in epilepsy plus. (13th March 2019)

• Record Type: Journal Article
• Authors: Coppola, Antonietta; Cellini, Elena; Stamberger, Hannah; Saarentaus, Elmo; Cetica, Valentina; Lal, Dennis; Djémié, Tania; Bartnik‐Glaska, Magdalena; Ceulemans, Berten; Helen Cross, J.; Deconinck, Tine; Masi, Salvatore De; Dorn, Thomas; Guerrini, Renzo; Hoffman‐Zacharska, Dorotha; Kooy, Frank; Lagae, Lieven; Lench, Nicholas; Lemke, Johannes R.; Lucenteforte, Ersilia; Madia, Francesca; Mefford, Heather C.; Morrogh, Deborah; Nuernberg, Peter; Palotie, Aarno; Schoonjans, An‐Sofie; Striano, Pasquale; Szczepanik, Elzbieta; Tostevin, Anna; Vermeesch, Joris R.; Van Esch, Hilde; Van Paesschen, Wim; Waters, Jonathan J; Weckhuysen, Sarah; Zara, Federico; De Jonghe, Peter; Sisodiya, Sanjay M.; Marini, Carla;
• Other Names: Lehesjioki Anna‐Elina investigator.; Craiu Dana investigator.; Talvik Tiina investigator.; Caglayan Hande investigator.; Serratosa Jose investigator.; Sterbova Katalin investigator.; Møller Rikke S. investigator.; Hjalgrim Helle investigator.; Lerche Holger investigator.; Weber Yvonne investigator.; Helbig Ingo investigator.; von Spiczak Sarah investigator.; Barba Carmen investigator.; Bogaerts Anneleen investigator.; Boni Antonella investigator.; Galizia Elisabeth Caruana investigator.; Chiari Sara investigator.; Di Gacomo Gianpiero investigator.; Ferrari Annarita investigator.; Guarducci Silvia investigator.; Giglio Sabrina investigator.; Holmgren Philip investigator.; Leu Costin investigator.; Melani Federico investigator.; Novara Francesca investigator.; Pantaleo Marilena investigator.; Peeters Elke investigator.; Pisano Tiziana investigator.; Rosati Anna investigator.; Sander Josemir investigator.; Schoeler Natasha investigator.; Stankiewicz Pawel investigator.; Striano Salvatore investigator.; Suls Arvid investigator.; Traverso Monica investigator.; Vandeweyer Geert investigator.; Van Dijck Anke investigator.; Zuffardi Orsetta investigator.;
• Is Part Of: Epilepsia. Volume 60:issue 4(2019)
• Page Start: 689
• Page End: 706
• Publication Date: 2019-03-13
• Subjects: array CGH -- copy number variants -- epilepsy genes -- SNP array; Epilepsy -- Periodicals; 616.853
• DOI: 10.1111/epi.14683
• Languages: English
• ISSNs: 0013-9580

Abstract

Summary: 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.