Coppola, Antonietta, Cellini, Elena, Stamberger, Hannah, Saarentaus, Elmo ORCID: 0000-0002-8475-7187, Cetica, Valentina, Lal, Dennis, Djemie, Tania, Bartnik-Glaska, Magdalena, Ceulemans, Berten, Cross, J. Helen, Deconinck, Tine, De Masi, Salvatore, Dorn, Thomas, Guerrini, Renzo, Hoffman-Zacharska, Dorotha, Kooy, Frank ORCID: 0000-0003-2024-0485, Lagae, Lieven, Lench, Nicholas, Lemke, Johannes R., Lucenteforte, Ersilia ORCID: 0000-0001-5608-5902, Madia, Francesca, Mefford, Heather C., Morrogh, Deborah, Nuernberg, Peter, Palotie, Aarno, Schoonjans, An-Sofie, Striano, Pasquale ORCID: 0000-0002-6065-1476, Szczepanik, Elzbieta, Tostevin, Anna, Vermeesch, Joris R., Van Esch, Hilde, Van Paesschen, Wim, Waters, Jonathan J., Weckhuysen, Sarah ORCID: 0000-0003-2878-1147, Zara, Federico, Jonghe, Peter De, Sisodiya, Sanjay M., Marini, Carla, Lehesjioki, Anna-Elina, Craiu, Dana, Talvik, Tiina, Caglayan, Hande, Serratosa, Jose, Sterbova, Katalin, Moller, Rikke S., Hjalgrim, Helle, Lerche, Holger, Weber, Yvonne, Helbig, Ingo, von Spiczak, Sarah, Barba, Carmen, Bogaerts, Anneleen, Boni, Antonella, Galizia, Elisabeth Caruana, Chiari, Sara, Clementella, Claudia, Di Gacomo, Gianpiero, Ferrari, Annarita, Guarducci, Silvia, Giglio, Sabrina ORCID: 0000-0002-3954-326X, Holmgren, Philip, Leu, Costin, Mari, Francesco, Melani, Federico, Novara, Francesca, Pantaleo, Marilena, Peeters, Elke, Pisano, Tiziana ORCID: 0000-0001-8920-9078, Rosati, Anna ORCID: 0000-0002-8754-7214, Sander, Josemir, Schoeler, Natasha ORCID: 0000-0001-6202-1497, Stankiewicz, Pawel, Striano, Salvatore, Suls, Arvid, Traverso, Monica, Vandeweyer, Geert, Van Dijck, Anke ORCID: 0000-0002-6713-2943 and Zuffardi, Orsetta (2019). Diagnostic implications of genetic copy number variation in epilepsy plus. Epilepsia, 60 (4). S. 689 - 707. HOBOKEN: WILEY. ISSN 1528-1167

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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 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Coppola, AntoniettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cellini, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stamberger, HannahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saarentaus, ElmoUNSPECIFIEDorcid.org/0000-0002-8475-7187UNSPECIFIED
Cetica, ValentinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Djemie, TaniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartnik-Glaska, MagdalenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ceulemans, BertenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cross, J. HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deconinck, TineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Masi, SalvatoreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dorn, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guerrini, RenzoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffman-Zacharska, DorothaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kooy, FrankUNSPECIFIEDorcid.org/0000-0003-2024-0485UNSPECIFIED
Lagae, LievenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lench, NicholasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lemke, Johannes R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lucenteforte, ErsiliaUNSPECIFIEDorcid.org/0000-0001-5608-5902UNSPECIFIED
Madia, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mefford, Heather C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morrogh, DeborahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palotie, AarnoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoonjans, An-SofieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Striano, PasqualeUNSPECIFIEDorcid.org/0000-0002-6065-1476UNSPECIFIED
Szczepanik, ElzbietaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tostevin, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vermeesch, Joris R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Esch, HildeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Paesschen, WimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waters, Jonathan J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weckhuysen, SarahUNSPECIFIEDorcid.org/0000-0003-2878-1147UNSPECIFIED
Zara, FedericoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jonghe, Peter DeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sisodiya, Sanjay M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marini, CarlaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lehesjioki, Anna-ElinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Craiu, DanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Talvik, TiinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caglayan, HandeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Serratosa, JoseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sterbova, KatalinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moller, Rikke S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hjalgrim, HelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, YvonneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helbig, IngoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Spiczak, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barba, CarmenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bogaerts, AnneleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boni, AntonellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galizia, Elisabeth CaruanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chiari, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clementella, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Di Gacomo, GianpieroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferrari, AnnaritaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guarducci, SilviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giglio, SabrinaUNSPECIFIEDorcid.org/0000-0002-3954-326XUNSPECIFIED
Holmgren, PhilipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leu, CostinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mari, FrancescoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Melani, FedericoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Novara, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pantaleo, MarilenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peeters, ElkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pisano, TizianaUNSPECIFIEDorcid.org/0000-0001-8920-9078UNSPECIFIED
Rosati, AnnaUNSPECIFIEDorcid.org/0000-0002-8754-7214UNSPECIFIED
Sander, JosemirUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoeler, NatashaUNSPECIFIEDorcid.org/0000-0001-6202-1497UNSPECIFIED
Stankiewicz, PawelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Striano, SalvatoreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suls, ArvidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Traverso, MonicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vandeweyer, GeertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Dijck, AnkeUNSPECIFIEDorcid.org/0000-0002-6713-2943UNSPECIFIED
Zuffardi, OrsettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-152340
DOI: 10.1111/epi.14683
Journal or Publication Title: Epilepsia
Volume: 60
Number: 4
Page Range: S. 689 - 707
Date: 2019
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1528-1167
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DE-NOVO MUTATIONS; MOLECULAR CHARACTERIZATION; CHROMOSOMAL MICROARRAY; ILAE COMMISSION; ONSET EPILEPSY; RORB GENE; PATIENT; ENCEPHALOPATHY; DISABILITIES; PHENOTYPEMultiple languages
Clinical NeurologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15234

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