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Evidence for linkage of adolescent-onset idiopathic generalized epilepsies to chromosome 8-and genetic heterogeneity.

ABSTRACT: Several loci and candidate genes for epilepsies or epileptic syndromes map or have been suggested to map to chromosome 8. We investigated families with adolescent-onset idiopathic generalized epilepsy (IGE), for linkage to markers spanning chromosome 8. The IGEs that we studied included juvenile myoclonic epilepsy (JME), epilepsy with only generalized tonic-clonic seizures occurring either randomly during the day (random grand mal) or on awakening (awakening grand mal), and juvenile absence epilepsy (JAE). We looked for a gene common to all these IGEs, but we also investigated linkage to specific subforms of IGE. We found evidence for linkage to chromosome 8 in adolescent-onset IGE families in which JME was not present. The maximum multipoint LOD score was 3.24 when family members with IGE or generalized spike-and-waves (SW) were considered affected. The LOD score remained very similar (3.18) when clinically normal family members with SW were not considered to be affected. Families with either pure grand mal epilepsy or absence epilepsy contributed equally to the positive LOD score. The area where the LOD score reaches the maximum encompasses the location of the gene for the beta3-subunit of the nicotinic acetylcholine receptor (CHRNB3), thus making this gene a possible candidate for these specific forms of adolescent-onset IGE. The data excluded linkage of JME to this region. These results indicate genetic heterogeneity within IGE and provide no evidence, on chromosome 8, for a gene common to all IGEs.

SUBMITTER: Durner M

PROVIDER: S-EPMC1377879 | biostudies-other | 1999 May

REPOSITORIES: biostudies-other

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Evidence for linkage of adolescent-onset idiopathic generalized epilepsies to chromosome 8-and genetic heterogeneity.

Durner M M Zhou G G Fu D D Abreu P P Shinnar S S Resor S R SR Moshe S L SL Rosenbaum D D Cohen J J Harden C C Kang H H Wallace S S Luciano D D Ballaban-Gil K K Klotz I I Dicker E E Greenberg D A DA

American journal of human genetics 19990501 5

Several loci and candidate genes for epilepsies or epileptic syndromes map or have been suggested to map to chromosome 8. We investigated families with adolescent-onset idiopathic generalized epilepsy (IGE), for linkage to markers spanning chromosome 8. The IGEs that we studied included juvenile myoclonic epilepsy (JME), epilepsy with only generalized tonic-clonic seizures occurring either randomly during the day (random grand mal) or on awakening (awakening grand mal), and juvenile absence epil ...[more]

PMID: 10205274

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Project description:Objective: The objective of this study is to explore the role of GRIN2A gene in idiopathic generalized epilepsies and the potential underlying mechanism for phenotypic variation. Methods: Whole-exome sequencing was performed in a cohort of 88 patients with idiopathic generalized epilepsies. Electro-physiological alterations of the recombinant N-methyl-D-aspartate receptors (NMDARs) containing GluN2A mutants were examined using two-electrode voltage-clamp recordings. The alterations of protein expression were detected by immunofluorescence staining and biotinylation. Previous studies reported that epilepsy related GRIN2A missense mutations were reviewed. The correlation among phenotypes, functional alterations, and molecular locations was analyzed. Results: Three novel heterozygous missense GRIN2A mutations (c.1770A > C/p.K590N, c.2636A > G/p.K879R, and c.3199C > T/p.R1067W) were identified in three unrelated cases. Electrophysiological analysis demonstrated R1067W significantly increased the current density of GluN1/GluN2A NMDARs. Immunofluorescence staining indicated GluN2A mutants had abundant distribution in the membrane and cytoplasm. Western blotting showed the ratios of surface and total expression of the three GluN2A-mutants were significantly increased comparing to the wild type. Further analysis on the reported missense mutations demonstrated that mutations with severe gain-of-function were associated with epileptic encephalopathy, while mutations with mild gain of function were associated with mild phenotypes, suggesting a quantitative correlation between gain-of-function and phenotypic severity. The mutations located around transmembrane domains were more frequently associated with severe phenotypes and absence seizure-related mutations were mostly located in carboxyl-terminal domain, suggesting molecular sub-regional effects. Significance: This study revealed GRIN2A gene was potentially a candidate pathogenic gene of idiopathic generalized epilepsies. The functional quantitative correlation and the molecular sub-regional implication of mutations helped in explaining the relatively mild clinical phenotypes and incomplete penetrance associated with GRIN2A variants.

Project description:Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8-13.2; chi(2) = 26.7; 1 degree of freedom; P = 2.4 x 10(-7)). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8-13.2; P = 4.2 x 10(-4)) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3-74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.

Dataset Information

Evidence for linkage of adolescent-onset idiopathic generalized epilepsies to chromosome 8-and genetic heterogeneity.

Publications

Evidence for linkage of adolescent-onset idiopathic generalized epilepsies to chromosome 8-and genetic heterogeneity.

Similar Datasets

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