Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy

Rikke S Møller; Yvonne G Weber; Laura L Klitten; Holger Trucks; Hiltrud Muhle; Wolfram S Kunz; Heather C Mefford; Andre Franke; Monika Kautza; Peter Wolf; Dieter Dennig; Stefan Schreiber; Ina-Maria Rückert; H-Erich Wichmann; Jan P Ernst; Claudia Schurmann; Hans J Grabe; Niels Tommerup; Ulrich Stephani; Holger Lerche; Helle Hjalgrim; Ingo Helbig; Thomas Sander; EPICURE Consortium

doi:10.1111/epi.12078

Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy

Rikke S Møller, Yvonne G Weber, Laura L Klitten, Holger Trucks, Hiltrud Muhle, Wolfram S Kunz, Heather C Mefford, Andre Franke, Monika Kautza, Peter Wolf, Dieter Dennig, Stefan Schreiber, Ina-Maria Rückert, H-Erich Wichmann, Jan P Ernst, Claudia Schurmann, Hans J Grabe, Niels Tommerup, Ulrich Stephani, Holger LercheHelle Hjalgrim, Ingo Helbig, Thomas Sander, EPICURE Consortium

Medical Genetics Program

44 Citations (Scopus)

Abstract

Purpose: Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods: We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings: We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92-51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance: We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

Original language	English
Journal	Epilepsia
Volume	54
Issue number	2
Pages (from-to)	256-64
Number of pages	9
ISSN	0013-9580
DOIs	https://doi.org/10.1111/epi.12078
Publication status	Published - 1 Feb 2013

Keywords

Adult
Age of Onset
Anticonvulsants
Case-Control Studies
Cell Adhesion Molecules, Neuronal
DNA Copy Number Variations
Electroencephalography
Epilepsy, Generalized
Exons
Family
Female
Fructose
Gene Deletion
Genotype
Humans
Infant
Male
Microarray Analysis
Middle Aged
Nerve Tissue Proteins
Neuropsychological Tests
Odds Ratio
Pedigree
Triazines
Valproic Acid

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10.1111/epi.12078

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Møller, R. S., Weber, Y. G., Klitten, L. L., Trucks, H., Muhle, H., Kunz, W. S., Mefford, H. C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I-M., Wichmann, H-E., Ernst, J. P., Schurmann, C., Grabe, H. J., Tommerup, N., Stephani, U., ... EPICURE Consortium (2013). Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy. Epilepsia, 54(2), 256-64. https://doi.org/10.1111/epi.12078

Møller, RS, Weber, YG, Klitten, LL, Trucks, H, Muhle, H, Kunz, WS, Mefford, HC, Franke, A, Kautza, M, Wolf, P, Dennig, D, Schreiber, S, Rückert, I-M, Wichmann, H-E, Ernst, JP, Schurmann, C, Grabe, HJ, Tommerup, N, Stephani, U, Lerche, H, Hjalgrim, H, Helbig, I, Sander, T & EPICURE Consortium 2013, 'Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy', Epilepsia, vol. 54, no. 2, pp. 256-64. https://doi.org/10.1111/epi.12078

@article{0a40163241f94d2d8c008b34369b7ca9,

title = "Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy",

abstract = "Purpose: Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods: We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings: We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92-51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance: We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.",

keywords = "Adult, Age of Onset, Anticonvulsants, Case-Control Studies, Cell Adhesion Molecules, Neuronal, DNA Copy Number Variations, Electroencephalography, Epilepsy, Generalized, Exons, Family, Female, Fructose, Gene Deletion, Genotype, Humans, Infant, Male, Microarray Analysis, Middle Aged, Nerve Tissue Proteins, Neuropsychological Tests, Odds Ratio, Pedigree, Triazines, Valproic Acid",

author = "M{\o}ller, {Rikke S} and Weber, {Yvonne G} and Klitten, {Laura L} and Holger Trucks and Hiltrud Muhle and Kunz, {Wolfram S} and Mefford, {Heather C} and Andre Franke and Monika Kautza and Peter Wolf and Dieter Dennig and Stefan Schreiber and Ina-Maria R{\"u}ckert and H-Erich Wichmann and Ernst, {Jan P} and Claudia Schurmann and Grabe, {Hans J} and Niels Tommerup and Ulrich Stephani and Holger Lerche and Helle Hjalgrim and Ingo Helbig and Thomas Sander and {EPICURE Consortium}",

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year = "2013",

month = feb,

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doi = "10.1111/epi.12078",

language = "English",

volume = "54",

pages = "256--64",

journal = "Epilepsia",

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TY - JOUR

T1 - Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy

AU - Møller, Rikke S

AU - Weber, Yvonne G

AU - Klitten, Laura L

AU - Trucks, Holger

AU - Muhle, Hiltrud

AU - Kunz, Wolfram S

AU - Mefford, Heather C

AU - Franke, Andre

AU - Kautza, Monika

AU - Wolf, Peter

AU - Dennig, Dieter

AU - Schreiber, Stefan

AU - Rückert, Ina-Maria

AU - Wichmann, H-Erich

AU - Ernst, Jan P

AU - Schurmann, Claudia

AU - Grabe, Hans J

AU - Tommerup, Niels

AU - Stephani, Ulrich

AU - Lerche, Holger

AU - Hjalgrim, Helle

AU - Helbig, Ingo

AU - Sander, Thomas

AU - EPICURE Consortium

PY - 2013/2/1

Y1 - 2013/2/1

N2 - Purpose: Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods: We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings: We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92-51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance: We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

AB - Purpose: Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods: We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings: We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92-51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance: We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

KW - Adult

KW - Age of Onset

KW - Anticonvulsants

KW - Case-Control Studies

KW - Cell Adhesion Molecules, Neuronal

KW - DNA Copy Number Variations

KW - Electroencephalography

KW - Epilepsy, Generalized

KW - Exons

KW - Family

KW - Female

KW - Fructose

KW - Gene Deletion

KW - Genotype

KW - Humans

KW - Infant

KW - Male

KW - Microarray Analysis

KW - Middle Aged

KW - Nerve Tissue Proteins

KW - Neuropsychological Tests

KW - Odds Ratio

KW - Pedigree

KW - Triazines

KW - Valproic Acid

U2 - 10.1111/epi.12078

DO - 10.1111/epi.12078

M3 - Journal article

C2 - 23294455

SN - 0013-9580

VL - 54

SP - 256

EP - 264

JO - Epilepsia

JF - Epilepsia

IS - 2

ER -

Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy

Abstract

Keywords

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