Human Molecular Genetics, 2000, Vol. 9, No. 10 1465-1472
© 2000 Oxford University Press
Genome search for susceptibility loci of common idiopathic generalised epilepsies
Epilepsy Genetics Group, Department of Neurology, University Hospital Charité, Campus Virchow Clinic, Humboldt University of Berlin, Augustenburger Platz 1, 13353 Berlin, Germany, 1Gene Mapping Centre, Max Delbrueck Centre, Robert-Roessle Str. 10, Berlin, Germany, 2Italian League against Epilepsy Collaborative Group on Genetics, Via Foscolo 7, 40123 Bologna, Italy, 3Association pour la Recherche sur la Génétique des Epilepsies, Hôpital Saint Vincent de Paul, 82 avenue Denfert Rochereau, 75674 Paris cedex 14, France, 4Généthon, 1 bis rue de l’Internationale, 91000 Evry, France, 5European Concerted Action on the Genetic Analysis of Epilepsy, Department of Paediatrics, Royal Free and University College Medical School, University College London, Gower Street Campus, The Rayne Institute, 5 University Street, London WC1E 6JJ, UK and 6Dutch Research Group on Juvenile Myoclonic Epilepsy and Idiopathic Generalised Epilepsy, MGC-Department of Clinical Genetics, Erasmus University Rotterdam, dr. Molewaterplein 50, 3000 DR Rotterdam, The Netherlands.
Received 11 February 2000; Revised and Accepted 2 April 2000 .
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSAPPENDIXREFERENCES |
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Genetic factors play a major role in the aetiology of idiopathic generalised epilepsies (IGEs). The present genome scan was designed to identify susceptibility loci that predispose to a spectrum of common IGE syndromes. Our collaborative study included 130 IGE-multiplex families ascertained through a proband with either an idiopathic absence epilepsy or juvenile myoclonic epilepsy, and one or more siblings affected by an IGE trait. In total, 413 microsatellite polymorphisms were genotyped in 617 family members. Non-parametric multipoint linkage analysis, using the GeneHunter program, provided significant evidence for a novel IGE susceptibility locus on chromosome 3q26 (ZNPL = 4.19 at D3S3725; P = 0.000017) and suggestive evidence for two IGE loci on chromosome 14q23 (ZNPL = 3.28 at D14S63; P = 0.000566), and chromosome 2q36 (ZNPL = 2.98 at D2S1371; P = 0.000535). The present linkage findings provide suggestive evidence that at least three genetic factors confer susceptibility to generalised seizures in a broad spectrum of IGE syndromes. The chromosomal segments identified harbour several genes involved in the regulation of neuronal ion influx which are plausible candidates for mutation screening.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSAPPENDIXREFERENCES |
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Epilepsy comprises a heterogeneous group of seizure disorders, affecting about 3% of the population during their life-times (1). Genetic factors play a major role in the aetiology of idiopathic generalised epilepsy (IGE), which accounts for 40% of all epilepsies (2–4). IGE comprises seven clinically delineated syndromes with age-related onset (5). Childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE) and juvenile myoclonic epilepsy (JME) represent the most common IGE subtypes (6,7). The leading seizure types of these IGE syndromes are absence seizures (CAE and JAE) and bilateral myoclonic seizures on awakening (JME). The electro-encephalographic signature of IGE seizures is characterised by generalised spike-wave discharges (GSW-EEG), which reflect a synchronised hyperexcitability state of thalamo-cortico-thalamic circuits (8,9).
The common IGE syndromes display a complex pattern of inheritance, suggesting that several genetic factors contribute to the genetic liability to generalised seizures (2–4). The recurrence risk of the common IGE syndromes ranges from 70% to 95% in monozygotic twins and is 10- to15-fold greater than for first-degree relatives (5–8%), and more than 100-fold greater than the prevalence of 0.6% in the general population (ratio of sibling risk to population prevalence: 
S 
8) (3). However, CAE, JAE and JME cluster in families, and, frequently, absence seizures are followed by myoclonic seizures in the same IGE patient in an age-dependent manner (7,10–13). These findings support the neurobiological concept that the common IGE subtypes share an overlapping genetic predisposition (3,10,12,13), and that the age-related expression of various seizure types arises from a genetically determined impairment of brain maturation or is influenced by the stage of brain maturation (14).
Progress in the positional cloning of epilepsy genes in monogenic forms of idiopathic epilepsies provides emerging evidence that these seizure traits arise from mutations in genes encoding ion channels (15,16). In humans, epilepsy genes of three rare idiopathic epilepsies with autosomal dominant mode of inheritance have been identified so far. Mutations in two voltage-gated potassium channel genes (KCNQ2 and KCNQ3) cause benign familial neonatal convulsions (17–19). In at least two families autosomal dominant nocturnal frontal lobe epilepsy arises from mutations in the gene encoding the 
4 subunit of the neuronal nicotinic acetylcholine receptor subunit (CHRNA4) (20,21). A mutation in the voltage-gated sodium channel ß1 gene (SCN1B) confers susceptibility to febrile seizures and generalised epilepsies (GEFS+) in a large Australian family (22). In mice, four autosomal recessive models of absence epilepsy (tottering, lethargic, stargazer and slow wave mutant mice) arise from mutations in genes encoding three types of calcium channel subunits (Cch1a, Cchb4, Cacng2) and a sodium–hydrogen ion exchanger (Nhe1) (23). These key findings provide new insights into the molecular pathways of epileptogenesis, and there is emerging evidence that ion channel mutations may be a common underlying mechanism of idiopathic epilepsies. However, it remains to be determined to what degree mutations in ion channel genes play a role in the complex molecular pathways of the common idiopathic epilepsy syndromes.
Two major challenges confront the positional cloning of susceptibility genes for the common IGE syndromes; complex inheritance and genetic heterogeneity (24). Until now, several tentative loci predisposing to complex IGE traits have been mapped to the chromosomal segments 6p11 (25), 6p21.3 (26–30), 8p11 (31), 8q24 (32,33) and 15q14 (34). However, replication studies failed to establish unequivocal linkage relationships and trait-causing mutations have not been identified so far (25,28–30,35–38). For the dissection of the complex genetic factors underlying the common IGE traits, large samples of clinically well characterised multiplex families are required and a systematic search of the whole genome is necessary. In the present collaborative genome scan, five European research groups have combined their efforts to conduct the first genome-wide search for IGE susceptibility loci in the largest sample of IGE-multiplex families (n = 130) investigated so far. Our linkage study was designed to test the neurobiological hypothesis that shared genetic factors contribute to the epileptogenesis of the common IGE syndromes.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSAPPENDIXREFERENCES |
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In total, 241 180 genotypes were assessed, accounting for 94.6% of the possible genotypes. The average marker distance of the 383 screening markers was 9.5 ± 2.8 cM (greatest marker distance was 17.8 cM). A mean information content of 0.708 ± 0.086 (range: 0.433–0.957) was obtained throughout the genome-wide multipoint GeneHunter analysis. The parametric and non-parametric linkage analyses were based only on the genotypic information of affected individuals (affecteds-only analyses).
In total, parametric two-point linkage analyses revealed seven loci (Table 1), providing suggestive (Z >1.9) or significant (Z >3.3) evidence for linkage. Significant evidence for linkage was found at two adjacent markers D3S1574 (Zmax = 4.43 at 
max = 0.14) and D3S3725 (Zmax = 3.31 at max = 0.18), in the chromosomal region 3q26, assuming a broad affectedness model, an autosomal dominant mode of inheritance and genetic homogeneity. Furthermore, suggestive evidence for linkage was obtained at a cluster of three adjacent markers (D2S371, D2S143 and D2S2382) in the chromosomal region 2q36, assuming an autosomal dominant mode of inheritance and genetic heterogeneity. In addition, LOD scores >1.9 were found at the loci D15S165 in the chromosomal region 15q14 (Zmax = 2.18 at max = 0.18) and D19S414 in the chromosomal region 19q12 (HLODmax = 2.78 at max = 0.00, = 0.35), assuming an autosomal recessive mode of inheritance.
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The parametric and non-parametric linkage results of the genome-wide GeneHunter multipoint analyses are presented in Figure 1. Figure 1a and b show the genome-wide type-I error rates (P values) of the non-parametric multipoint analyses (Z-all statistic) for narrow (Fig. 1a) and broad (Fig. 1b) affectedness models, respectively. Using a screening type-I error rate of P < 7.4 x 10–4 (suggestive linkage), three regions provided evidence for linkage to IGE-traits. The lowest P values for IGE traits were obtained in the chromosomal regions: 3q26 [ZNPL = 4.191, P = 0.000017 at D3S3725; broad affectedness model (Fig. 2a)], 14q23 [ZNPL = 3.282, P = 0.000566 at D14S63; broad affectedness model (Fig. 2b)], 2q36.1 [ZNPL = 2.980, P = 0.000535 at D2S1371; narrow affectedness model (Fig. 2c)]. To evaluate whether the identified IGE loci confer susceptibility to either a broad IGE spectrum or more restricted IGE subtypes, we performed linkage analyses at the linkage hot-spots (3q26, 14q23 and 2q36) in two distinct family subsets selected by the presence (n = 54) or absence (n = 76) of a family member with JME. For each of the three candidate regions, both subsets of families provided supportive evidence for linkage (Fig. 2).
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Likewise (Fig. 1c and d), maximum parametric multipoint HLOD scores >1.9 (suggestive evidence for linkage) were found in the same chromosomal regions, 3q26 (HLOD = 3.780 at D3S3725, assuming the broad affectedness model, an autosomal dominant mode of inheritance and 40% of linked families), 14q23 (HLOD = 2.428 at D14S63, assuming the broad affectedness model, an autosomal dominant mode of inheritance and 33% of linked families), 2q36.1 (HLOD = 2.196 at D2S1371, assuming the narrow affectedness model, an autosomal dominant mode of inheritance, and 38% of linked families). In addition, suggestive evidence for linkage was obtained in the chromosomal region 6q13 (HLOD = 2.447 telomeric to D6S286, assuming the broad affectedness model, an autosomal dominant mode of inheritance, and 35% of linked families; ZNPL = 2.998 at D6S286, P = 0.00145). None of the maximum HLOD scores obtained under an autosomal recessive mode of inheritance exceeded those obtained under an autosomal dominant mode of inheritance in the chromosomal regions, providing suggestive evidence for linkage.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSAPPENDIXREFERENCES |
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This is the first systematic genome scan performed on common IGE syndromes. Five European research groups combined their efforts to collect the largest sample of IGE-multiplex families investigated so far. The present study was designed to search for susceptibility loci underlying a shared genetic predisposition to common IGE syndromes. To narrow the phenotypic IGE spectrum, the families were ascertained through a proband affected by a clinically unequivocally characterised IGE syndrome (CAE, JAE or JME) for which an overlapping genetic predisposition has been suggested on the basis of clinical and epidemiological studies (10–13). Furthermore, the families selected contained one or more affected siblings with an IGE trait to increase the chance of detecting single major susceptibility factors.
Our linkage results provide significant evidence for a novel IGE susceptibility locus on chromosome 3q26 and suggestive evidence for two IGE loci on chromosomes 14q23 and 2q36.1. The strongest evidence for identical-by-descent (IBD) allele-sharing was achieved for the chromosomal segment 3q26 at the marker D3S3725 (ZNPL = 4.19; P = 0.000017), assuming the broad model of affectedness. Consistently, parametric multipoint linkage analyses provided significant evidence for linkage at the same locus, assuming an autosomal dominant mode of inheritance. In addition, suggestive evidence for linkage was found for two susceptibility loci on 14q23 and 2q36.1 under the non-parametric as well as under the parametric multipoint analyses. Furthermore, a possible susceptibility locus predisposing to the broad IGE trait model was indicated on chromosome 6q13 by parametric multipoint linkage analyses. For each of the three candidate regions (3q26, 14q23, 2q36.1), supportive evidence for linkage was obtained in two distinct subsets of families selected by the presence or absence of a family member with JME (Fig. 2). Accordingly, these data confirm that in particular, the IGE locus on chromosome 3q26 is involved in the epileptogenesis of a wide range of IGE syndromes.
In addition to the multipoint analyses, parametric two-point linkage results revealed suggestive evidence for linkage to two markers (Table 1), D15S165 and D19S414, that merit further attention because of previous linkage findings to these markers (22,34,39). D15S165 maps close to a region on chromosome 15q14 to which a major susceptibility locus for JME has been localised in families with one or more JME members (34). D19S414 is located on chromosome 19q12 close to the voltage-gated sodium channel ß1 subunit gene (SCN1B). A loss-of-function mutation in the SCN1B gene was shown to cause febrile seizures and generalised epilepsies (GEFS+) in a large Australian family (22). Moreover, the autosomal dominant epilepsy syndrome, benign familial infantile convulsions, has been mapped to chromosome 19 with a maximum two-point LOD score of Z = 6.36 at D19S414 (39). However, multipoint linkage analyses, including additional markers in the regions of interest, did not support evidence for linkage to these regions in the present study (Fig. 1).
The molecular genetic dissection of common complex traits is hampered by several unresolved analytical problems, such as incomplete penetrance, phenocopies, genetic imprinting, a considerable variance in the genotype–phenotype relationship and genetic heterogeneity (24). Although locus heterogeneity is likely in the aetiology of IGE syndromes, the test for locus heterogeneity (HOMOG program) did not indicate evidence for locus heterogeneity at any marker position. The failure to detect locus heterogeneity results from the investigation of predominantly (82%) nuclear families. Accordingly, the information content of each nuclear family is too small to provide unequivocal evidence for or against linkage. Therefore, the power of the test for locus heterogeneity is rather low in the present family sample. Furthermore, simulation studies have shown that chance variation in the location estimate is remarkably wide in linkage studies of complex traits (40). Moreover, the location estimate is blurred by several confounding factors, such as incomplete penetrance, phenocopies, genetic heterogeneity and the assumption of an incorrect trait model. Taking into account that our linkage analyses are based only on the genotypic information of affected individuals, and that the IBD scoring function of the GeneHunter program displays a reduced power in the presence of incomplete data (41), the linkage methods applied in the present study are conservative. It is important to note that we did not maximise parametric linkage analyses over a wide range of inheritance vectors. Irrespective, of whether we applied non-parametric or parametric linkage analyses, consistent evidence for linkage was obtained at the same chromosomal regions on 3q26, 14q23 and 2q36. Nevertheless, our explorative approach, using two affectedness models and 383 markers for the genome search, increases the risk of false-positive linkage findings due to multiple testing. Therefore, the three IGE susceptibility loci found should be regarded as tentative linkage findings that require further confirmation. However, accelerating advances in the sequence information of the human genome and progress in mutation screening techniques will change the present positional cloning strategies towards sequence analyses of plausible candidate genes in order to overcome the unresolved analytical problems in linkage mapping of complex traits.
Emerging evidence suggests that monogenic forms of idiopathic epilepsies in humans and mice and other paroxysmal disorders are caused by loss-of-function mutations in genes encoding ion channels (15,16,42,43). Ion channel genes involved in human epileptogenesis include those encoding neuronal nicotinic acetylcholine receptor subunits (CHRNA4) and voltage-gated potassium (KCNQ2, KCNQ3) and sodium channels (SCN1B). Furthermore, genes encoding proteins involved in the low-threshold calcium-dependent oscillatory properties of the reticular thalamic nucleus seem to play a critical role in generating recurrent intrathalamic burst activity that represents a possible primary dysfunction underlying the expression of bilateral synchronous spike and wave discharges (9,43). Accordingly, genes involved in the regulation of neuronal ion homeostasis represent plausible candidates for IGE susceptibility genes (15,16,42,43). The identified chromosomal segments harbour several genes involved in the regulation of neuronal ion influx. Promising candidate genes for mutation screening studies include the voltage-gated potassium channel, KCNA1B (3q26.1), the voltage-gated chloride channel, CLCN2 (3q27-q28), the sodium–calcium exchanger, SLC8A3 (14q21–31), and the chloride–bicarbonate anion exchanger, SLC4A3 (2q36).
In summary, our results suggest that at least three genetic factors confer liability to generalised seizures in a broad spectrum of IGE syndromes. The present linkage findings pin-point target regions for the positional cloning of IGE susceptibility loci. The detection of the underlying mutations will provide clues to elucidate the complex molecular pathways of epileptogenesis, and, finally, will help to develop rational treatment strategies.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSAPPENDIXREFERENCES |
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Family ascertainment and clinical characterisation
The study protocol was approved by the institutional review boards of the participating European centres. Written informed consent was obtained from all participants. The present study included 130 families with 694 members of whom 617 individuals were genotyped. Inclusion criteria were: (i) proband with either idiopathic absence epilepsy or JME; (ii) one or more siblings with either one or more unprovoked (idiopathic) generalised seizures or generalised spike-wave discharges in the standard EEG (GSW-EEG); (iii) both parents, if available, or sufficient siblings to reconstruct the missing parental genotypes. The total sample of 130 IGE-multiplex families was derived from five European centres for epilepsy genetics: England (n = 16), France (n = 32), Germany (n = 50), Italy (n = 20) and The Netherlands (n = 12). Fifty four families were ascertained through a proband with JME, 23 families through a proband with JAE and 53 families through a proband with CAE. Clinical and EEG data for each participant were documented in standardised anonymous protocols that were reviewed by experienced reference epileptologists at the recruiting epilepsy centre. The diagnosis of epilepsies and epileptic syndromes were performed according to diagnostic criteria based on the revised ‘Classification of Epilepsies and Epileptic Syndromes of the International League Against Epilepsy’ (5–7).
Of the 130 families, 107 (82%) were nuclear families and 23 (18%) families were multigenerational . In 40% of the families, one of the parents was affected by an epilepsy-trait. The epilepsy syndromes and epileptic seizures in 351 clinically affected family members included (one major epilepsy syndrome or seizure type per individual): 116 CAE, 59 JAE, 95 JME, six idiopathic absence epilepsies, 50 epilepsies with generalised tonic–clonic seizures, seven epilepsies with generalised tonic–clonic seizures on awakening, seven single unprovoked generalised tonic–clonic seizure, one photosensitive epilepsy, one Lennox–Gastaut syndrome, one West syndrome, three symptomatic epilepsies and five febrile convulsions. Furthermore, 20 clinically unaffected family members exhibited generalised spike-wave complexes in their standard EEG (GSW-EEG). Further details about the pedigrees and the syndromic classification of the affected family members are available at http://www.charite.de/epileptologie/Forschungsgruppen/genetik/downlinks.html (pdf file). The diagnostic classification of the epilepsy phenotypes was performed before genotyping.
To evaluate whether the IGE loci identified confer susceptibility to a broad IGE spectrum or more restricted IGE subtypes, post-hoc linkage analyses were performed at the linkage hot-spots in two distinct family subsets selected by the presence (n = 54) or absence (n = 76) of a family member with JME.
Genotyping
DNA was isolated from peripheral white blood cells or lymphoblastoid cell lines using standard methods. The genotyping of dinucleotide polymorphisms was conducted at the Gene Mapping Centre at the Max-Delbrueck Centre in Berlin, using a microsatellite mapping panel (http://wwwmsz.mdc-berlin.de/marker.html ) that is based on microsatellites from the Généthon reference map (44). In total, 383 dinucleotide polymorphisms were analysed in the systematic genome scan, covering the entire autosomal genome, with an average spacing of 9.5 ± 2.8 cM. In addition, 30 microsatellite polymorphisms were genotyped for enhancing informativity in areas suggestive of linkage. Markers of the X-chromosome were not included. Markers were amplified on microtitre plates on Tetrad PCR machines (MJ Research Inc., Waltham, MA). PCR pools were separated on ABI 377 automatic sequencers, and genotypes were scored using Genescan version 2.2 and Genotyper version 2.0 software (ABI). All genotypes were checked for Mendelian segregation using the Unknown algorithm from the Linkage program package (45). All allele sizes were standardised to known Centre d’Etudes du Polymorphisme Humain (CEPH) control individuals without knowledge of the disease status.
Models of affectedness
Family members were classified under two models of affectedness. Under the narrow model (NM), family members with either an idiopathic absence epilepsy or JME were considered to be affected (n = 276). In the broad model (BM), family members with either unprovoked generalised seizures or GSW-EEG were classified as affected (n = 360). The affectedness status of 11 individuals with epileptic seizures was regarded as unknown because their seizure types did not fit unambiguously into an IGE trait (one photosensitive epilepsy, one Lennox–Gastaut syndrome, one West syndrome, three symptomatic epilepsies and five febrile convulsions). The diagnostic status of the other family members was classified as
unknown (affecteds-only analyses). The affectedness status was determined before genotypes were assessed.
Linkage analysis
Two-point LOD scores were calculated using the Linkage program package (45). Single-locus approximation models were applied assuming either an autosomal dominant (AD) or recessive (AR) mode of inheritance (46). Linkage analysis was based only on the marker status of affected individuals. The affecteds-only analyses used took into account the fact that susceptibility alleles of complex traits are likely to be expressed with low penetrance. In addition, LOD scores were calculated for varying proportions () of linked families in order to maximise LOD scores under the assumption of locus heterogeneity (HLOD), using the program HOMOG implemented in the Linkage package (45). Frequencies of the susceptibility allele were estimated according to the trait prevalence (narrow model: 0.8%; broad model: 3.6%). A phenocopy rate of 0.01 was used throughout the analysis. LOD scores were calculated for equal recombination fractions () in both sexes (m = f). Allele frequencies of the microsatellite markers were determined from genotypes of unrelated founders of the investigated families.
Parametric and non-parametric multipoint linkage analyses were performed, using GeneHunter, version 2.0b (47). The non-parametric Z-all statistic estimates the statistical significance of sharing alleles IBD between all affected family members. The test statistic produced is expressed as NPL score (ZNPL) and provides the point-wise type-I error rate (P) by computing the exact probability distribution of the Z-all score under the null-hypothesis of no linkage. In addition, parametric linkage analyses were carried out by multipoint maximum-likelihood methods, implemented in the GeneHunter program. Power simulations by the program FastsLink (48) revealed average expected HLOD scores >3.6 under all parametric trait models, assuming a distance of 5 cM between marker and trait locus, and a proportion of 65% of families to be linked.
The significance levels applied in the present investigation are based on thresholds proposed by Lander and Kruglyak (49). Significance evidence for linkage: P = 2.2 x10–5 for non-parametric allele-sharing methods and a maximum LOD score of 3.3 for LOD score analysis. Suggestive evidence for linkage: P = 7.4 10–4 for non-parametric allele-sharing methods and a maximum LOD score of 1.9 for LOD score analysis.
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ACKNOWLEDGEMENTS |
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We thank all participating families for their help and all members of the clinical centres for their support. This work was supported by grants of the Deutsche Forschungsgemeinschaft (Sa434/2-1,-2,-3; Ep7/8-1) and the Stiftung Michael. The MDC Mikrosatellitenzentrum is supported by the German Genome Project (BMBF). The Dutch JME/IGE research group was supported by grants from the Dutch Epilepsy Fund (95-04), Stichting Vrienden van Kempenhaeghe and Epilepsy Centre S.E.I.N. (Heemstede-Zwolle). The Association pour la Recherche sur la Génétique des Epilepsies was supported by Généthon, Association Francaise contre les Myopathies (AFM ) and Sanofi. The Italian League against Epilepsy collaborative group on genetics is supported by Telethon, Italy (grant 213).
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APPENDIX |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSAPPENDIXREFERENCES |
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European Consortium on the Genetics of Idiopathic Generalised Epilepsy
Principal research groups
United Kingdom. European Concerted Action on the Genetic Analysis of Epilepsy, Department of Paediatrics, Royal Free and University College Medical School, University College London, Gower Street Campus, The Rayne Institute, 5 University Street, London WC1E 6JJ. R.M. Gardiner (coordinator), L. Bate, F.V. Elmslie, M. Rees, M.P. Williamson and W.P. Whitehouse.
Participating clinicians: M.L. Friis, M Kjeldsen, Denmark; J. Aicardi, France; A. Covanis, Greece; I. Olsson, A. Sundquist, Sweden; M. Kerr, A. Richens and S. Shorvon., United Kingdom.
France. Association pour la Recherche sur la Génétique des Epilepsies, Hôpital Saint Vincent de Paul, 82 avenue Denfert Rochereau, 75674 Paris cedex 14. O. Dulac (coordinator), C. Bulteau, A. Kaminska, D. Ville, C. Cieuta, D. Luna and F. Picard.Généthon, 1 bis rue de l’Internationale, 91000 Evry: J.-F. Prud’homme (coordinator).Participating clinicians: P. Abegg, D. Audry, N. Badinand, M. Baldy-Moulinier, P. Barth, M. Beaussart, C. Billard, O. Brocard, P. Bourdon, M. Combelles-Pruvot, H. Duclos, S. Gros, E. Hirsch, P. Huc, P. Lachenal, A. Lemoigne, M.-O. Livet, M.-N. Loiseau-Corvez, F. Mauguière, Y. Moene, G. Montagnier, E. Planque, P. Recoules, M. Revol, B. Rigaudière, G. Rudolf, R. Sahloul, J.-F. Savet, S.F. Secardin, V. Tarel, R. Texier and L. Vallée, France.
Germany. Epilepsy Genetics Group, Department of Neurology, University Hospital Charité, Campus Virchow Clinic, Humboldt University of Berlin, Augustenburger Platz 1, 13353 Berlin: T. Sander (coordinator), V. Kwiatkowski, M. Petzold, O. Riess, B. Schmitz and H. Schulz.Gene Mapping Centre, Max Delbrueck Centre, Robert-Roessle Str. 10, Berlin: A. Reis, K. Saar and T.F. Wienker.Participating clinicians: G. Bauer, U. Sailer, H. Steinboeck, Austria; A. Aksu, D. Dennig, C. Foerster, G. Gross-Selbeck, S. Noachtar, U. Runge, G. Rabending, Germany; S.N. Yeni, Turkey; A. Scaramelli, Uruguay and N. Rajsic, Yugoslavia.
Italy. Italian League against Epilepsy Collaborative Group on Genetics, Via Foscolo 7, 40123 Bologna: A. Bianchi (coordinator), E. Gennaro, C. Riggio and F. Zara.Participating clinicians: S. Binelli, R. Canger, C. Durisotti, F. De Falco, S. Franceschetti, T. Granata, A. Magauddo, D. Malamaci, M. Manfredi, A. Parmeggiani, P. Piccinelli, P. Rasmini, E. Santorum, M. Viri and M.R. Vitali, Italy.
The Netherlands. Dutch Research Group on Juvenile Myoclonic Epilepsy and Idiopathic Generalised Epilepsy, MGC-Department of Clinical Genetics, Erasmus University Rotterdam, dr. Molewaterplein 50, 3000 DR Rotterdam. D. Lindhout (coordinator), A. Bader, E.H.J.F. Boezeman, M. Gerard van Erp, A.M.A.J. Janssen, G.-J. de Haan, D.J.J. Halley, D.G.A. Kasteleijn-Nolst-Trenité, L.A. Sandkuijl and J. Witte.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +49 30 45060028, Fax: +49 30 45060938
§ These authors contributed equally to the present study.
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