Format

Send to

Choose Destination
PLoS Genet. 2015 May 7;11(5):e1005226. doi: 10.1371/journal.pgen.1005226. eCollection 2015 May.

Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies.

Author information

1
Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Department of Neuropediatrics, University Medical Center Giessen and Marburg, Giessen, Germany; EPICURE Consortium.
2
Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; EPICURE Consortium.
3
EPICURE Consortium; Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
4
EPICURE Consortium.
5
EPICURE Consortium; Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands; SEIN Epilepsy Institute in the Netherlands, Hoofddorp, The Netherlands.
6
EPICURE Consortium; Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany.
7
EPICURE Consortium; Department of Neurology, University of Munich Hospital-Großhadern, Munich, Germany.
8
EPICURE Consortium; Department of Epileptology, University Clinics Bonn, Bonn, Germany.
9
EPICURE Consortium; Department of Neurology, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany.
10
EPICURE Consortium; Department of Neurology, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany; Department of Neurology, Vivantes Humboldt-Klinikum, Berlin, Germany.
11
EPICURE Consortium; Department of Neuropediatrics, University Medical Center Schleswig-Holstein (Kiel Campus), Kiel, Germany.
12
EPICURE Consortium; Epilepsy-Center Hessen, Department of Neurology, Philipps-University Marburg, Marburg, Germany; Epilepsy Center Frankfurt Rhein-Main, Department of Neurology, Johann Wolfgang Goethe University Frankfurt, Frankfurt, Germany.
13
Department of Neuropediatrics, University Medical Center Giessen and Marburg, Giessen, Germany.
14
EPICURE Consortium; Department of Neurology, Medical University of Vienna, Vienna, Austria.
15
EPICURE Consortium; Department of Pediatrics and Neonatology, Medical University of Vienna, Vienna, Austria.
16
EPICURE Consortium; Department of Neurology, Danish Epilepsy Centre, Dianalund, Denmark; Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
17
EPICURE Consortium; Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
18
Institute of Epidemiology and Biobank Popgen, Christian Albrechts University, Kiel, Germany.
19
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
20
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, and Chair of Genetic Epidemiology, Ludwig-Maximilians-University, Munich, Germany.
21
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
22
Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University, Greifswald, Germany.
23
Department of Neurology, University Medicine Greifswald, Ernst Moritz Arndt University, Greifswald, Germany.
24
Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; EPICURE Consortium; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.

Abstract

Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.

PMID:
25950944
PMCID:
PMC4423931
DOI:
10.1371/journal.pgen.1005226
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center