Diagnostic implications of genetic copy number variation in epilepsy plus

Antonietta Coppola; Elena Cellini; Hannah Stamberger; Elmo Saarentaus; Valentina Cetica; Dennis Lal; Tania Djémié; Magdalena Bartnik-Glaska; Berten Ceulemans; J Helen Cross; Tine Deconinck; Salvatore De Masi; Thomas Dorn; Renzo Guerrini; Dorotha Hoffman-Zacharska; Frank Kooy; Lieven Lagae; Nicholas Lench; Johannes R Lemke; Ersilia Lucenteforte; Francesca Madia; Heather C Mefford; Deborah Morrogh; Peter Nuernberg; Aarno Palotie; An-Sofie Schoonjans; Pasquale Striano; Elzbieta Szczepanik; Anna Tostevin; Joris R Vermeesch; Hilde Van Esch; Wim Van Paesschen; Jonathan J Waters; Sarah Weckhuysen; Federico Zara; Peter De Jonghe; Sanjay M Sisodiya; Carla Marini; EuroEPINOMICS-RES Consortium; EpiCNV Consortium

doi:10.1111/epi.14683

Diagnostic implications of genetic copy number variation in epilepsy plus

Epilepsia. 2019 Apr;60(4):689-706. doi: 10.1111/epi.14683. Epub 2019 Mar 13.

Authors

Antonietta Coppola^{1

2

3}, Elena Cellini⁴, Hannah Stamberger^{5

6

7}, Elmo Saarentaus^{8

9

10}, Valentina Cetica⁴, Dennis Lal^{8

9

11

12

13}, Tania Djémié^{5

6}, Magdalena Bartnik-Glaska¹⁴, Berten Ceulemans¹⁵, J Helen Cross^{16

17

18}, Tine Deconinck^{5

6}, Salvatore De Masi¹⁹, Thomas Dorn²⁰, Renzo Guerrini⁴, Dorotha Hoffman-Zacharska¹⁴, Frank Kooy²¹, Lieven Lagae²², Nicholas Lench²³, Johannes R Lemke²⁴, Ersilia Lucenteforte²⁵, Francesca Madia²⁶, Heather C Mefford²⁷, Deborah Morrogh²³, Peter Nuernberg¹³, Aarno Palotie^{8

9

10}, An-Sofie Schoonjans¹⁵, Pasquale Striano²⁸, Elzbieta Szczepanik²⁹, Anna Tostevin^{1

2}, Joris R Vermeesch³⁰, Hilde Van Esch³⁰, Wim Van Paesschen³¹, Jonathan J Waters²³, Sarah Weckhuysen^{5

6

7}, Federico Zara²⁶, Peter De Jonghe^{5

6

7}, Sanjay M Sisodiya^{1

2}, Carla Marini⁴; EuroEPINOMICS-RES Consortium; EpiCNV Consortium

Collaborators

Affiliations

¹ Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, WC1N3BG, UK.
² The Chalfont Centre for Epilepsy, Chesham Lane, Chalfont St Peter, Bucks, UK.
³ Epilepsy Centre, Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy.
⁴ Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
⁵ Neurogenetics Group, Center for Molecular Neurology, VIB, 2650, Antwerp, Belgium.
⁶ Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
⁷ Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
⁸ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹⁰ Institute of Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
¹¹ Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, 44195, US.
¹² Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic, Cleveland, OH, 44195, US.
¹³ Cologne Center for Genomics, University of Cologne, Germany.
¹⁴ Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
¹⁵ Department of Neurology-Pediatric Neurology, University and University Hospital Antwerp, Antwerp, Belgium.
¹⁶ Neurology Department, Great Ormond Street Hospital, NHS Foundation Trust, London, UK.
¹⁷ Clinical Neuroscience, UCL GOSH Institute of Child Health, London, UK.
¹⁸ Young Epilepsy, Lingfield, UK.
¹⁹ Clinical Trial Office, Meyer Children's Hospital, Florence, Italy.
²⁰ Swiss Epilepsy Center, Bleulerstrasse 60, CH-8008, Switzerland.
²¹ Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
²² Department of Development and Regeneration, Section Pediatric Neurology, University Hospital KU Leuven, 3000, Leuven, Belgium.
²³ North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK.
²⁴ Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
²⁵ Department of Clinical and Experimental Medicine, University of Pisa, Italy, Clinical Trial Office, Meyer Children's Hospital, Florence, Italy.
²⁶ Neurogenetic Laboratory, Scientific Institute for Research, Hospitalisation and Health Care (IRCCS) G. Gaslini Institute, Genova, Italy.
²⁷ Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, USA.
²⁸ Pediatric Neurology and Muscular Diseases Unit, DINOGMI-Department of Neurosciences, Rehabilitation, Ophthalmology Genetics, Maternal and Child Health, University of Genoa, 'G. Gaslini' Institute, Genova, Italy.
²⁹ Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland.
³⁰ Center for Human Genetics, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
³¹ Department of Neurology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.

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.

Keywords: SNP array; array CGH; copy number variants; epilepsy genes.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Comorbidity
DNA Copy Number Variations
Epilepsy / complications
Epilepsy / genetics*
Genetic Predisposition to Disease
Genotype
Humans
Phenotype

Abstract

Publication types

MeSH terms

Grants and funding