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

Dennis Lal, Ann-Kathrin Ruppert, Holger Trucks, Herbert Schulz, Carolien G de Kovel, Dorothée Kasteleijn-Nolst Trenité, Anja C M Sonsma, Bobby P Koeleman, Dick Lindhout, Yvonne G Weber, Holger Lerche, Claudia Kapser, Christoph J Schankin, Wolfram S Kunz, Rainer Surges, Christian E Elger, Verena Gaus, Bettina Schmitz, Ingo Helbig, Hiltrud MuhleUlrich Stephani, Karl M Klein, Felix Rosenow, Bernd A Neubauer, Eva M Reinthaler, Fritz Zimprich, Martha Feucht, Rikke S Møller, Helle Hjalgrim, Peter De Jonghe, Arvid Suls, Wolfgang Lieb, Andre Franke, Konstantin Strauch, Christian Gieger, Claudia Schurmann, Ulf Schminke, Peter Nürnberg, Thomas Sander, EPICURE Consortium

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
Artikelnummere1005226
TidsskriftPLOS Genetics
Vol/bind11
Udgave nummer5
Antal sider21
ISSN1553-7390
DOI
StatusUdgivet - 2015

Fingeraftryk

epilepsy
gene
genes
hot spot
genomics
analysis
Single Nucleotide Polymorphism
risk factor
ancestry
brain
genome

Citer dette

Lal, D., Ruppert, A-K., Trucks, H., Schulz, H., de Kovel, C. G., Kasteleijn-Nolst Trenité, D., ... EPICURE Consortium (2015). Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. PLOS Genetics, 11(5), [e1005226]. https://doi.org/10.1371/journal.pgen.1005226
Lal, Dennis ; Ruppert, Ann-Kathrin ; Trucks, Holger ; Schulz, Herbert ; de Kovel, Carolien G ; Kasteleijn-Nolst Trenité, Dorothée ; Sonsma, Anja C M ; Koeleman, Bobby P ; Lindhout, Dick ; Weber, Yvonne G ; Lerche, Holger ; Kapser, Claudia ; Schankin, Christoph J ; Kunz, Wolfram S ; Surges, Rainer ; Elger, Christian E ; Gaus, Verena ; Schmitz, Bettina ; Helbig, Ingo ; Muhle, Hiltrud ; Stephani, Ulrich ; Klein, Karl M ; Rosenow, Felix ; Neubauer, Bernd A ; Reinthaler, Eva M ; Zimprich, Fritz ; Feucht, Martha ; Møller, Rikke S ; Hjalgrim, Helle ; De Jonghe, Peter ; Suls, Arvid ; Lieb, Wolfgang ; Franke, Andre ; Strauch, Konstantin ; Gieger, Christian ; Schurmann, Claudia ; Schminke, Ulf ; Nürnberg, Peter ; Sander, Thomas ; EPICURE Consortium. / Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. I: PLOS Genetics. 2015 ; Bind 11, Nr. 5.
@article{6357a6664e4c4b3d8daecdb054ead333,
title = "Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies",
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.",
author = "Dennis Lal and Ann-Kathrin Ruppert and Holger Trucks and Herbert Schulz and {de Kovel}, {Carolien G} and {Kasteleijn-Nolst Trenit{\'e}}, Doroth{\'e}e and Sonsma, {Anja C M} and Koeleman, {Bobby P} and Dick Lindhout and Weber, {Yvonne G} and Holger Lerche and Claudia Kapser and Schankin, {Christoph J} and Kunz, {Wolfram S} and Rainer Surges and Elger, {Christian E} and Verena Gaus and Bettina Schmitz and Ingo Helbig and Hiltrud Muhle and Ulrich Stephani and Klein, {Karl M} and Felix Rosenow and Neubauer, {Bernd A} and Reinthaler, {Eva M} and Fritz Zimprich and Martha Feucht and M{\o}ller, {Rikke S} and Helle Hjalgrim and {De Jonghe}, Peter and Arvid Suls and Wolfgang Lieb and Andre Franke and Konstantin Strauch and Christian Gieger and Claudia Schurmann and Ulf Schminke and Peter N{\"u}rnberg and Thomas Sander and {EPICURE Consortium}",
year = "2015",
doi = "10.1371/journal.pgen.1005226",
language = "English",
volume = "11",
journal = "P L o S Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "5",

}

Lal, D, Ruppert, A-K, Trucks, H, Schulz, H, de Kovel, CG, Kasteleijn-Nolst Trenité, D, Sonsma, ACM, Koeleman, BP, Lindhout, D, Weber, YG, Lerche, H, Kapser, C, Schankin, CJ, Kunz, WS, Surges, R, Elger, CE, Gaus, V, Schmitz, B, Helbig, I, Muhle, H, Stephani, U, Klein, KM, Rosenow, F, Neubauer, BA, Reinthaler, EM, Zimprich, F, Feucht, M, Møller, RS, Hjalgrim, H, De Jonghe, P, Suls, A, Lieb, W, Franke, A, Strauch, K, Gieger, C, Schurmann, C, Schminke, U, Nürnberg, P, Sander, T & EPICURE Consortium 2015, 'Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies', PLOS Genetics, bind 11, nr. 5, e1005226. https://doi.org/10.1371/journal.pgen.1005226

Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. / Lal, Dennis; Ruppert, Ann-Kathrin; Trucks, Holger; Schulz, Herbert; de Kovel, Carolien G; Kasteleijn-Nolst Trenité, Dorothée; Sonsma, Anja C M; Koeleman, Bobby P; Lindhout, Dick; Weber, Yvonne G; Lerche, Holger; Kapser, Claudia; Schankin, Christoph J; Kunz, Wolfram S; Surges, Rainer; Elger, Christian E; Gaus, Verena; Schmitz, Bettina; Helbig, Ingo; Muhle, Hiltrud; Stephani, Ulrich; Klein, Karl M; Rosenow, Felix; Neubauer, Bernd A; Reinthaler, Eva M; Zimprich, Fritz; Feucht, Martha; Møller, Rikke S; Hjalgrim, Helle; De Jonghe, Peter; Suls, Arvid; Lieb, Wolfgang; Franke, Andre; Strauch, Konstantin; Gieger, Christian; Schurmann, Claudia; Schminke, Ulf; Nürnberg, Peter; Sander, Thomas; EPICURE Consortium.

I: PLOS Genetics, Bind 11, Nr. 5, e1005226, 2015.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies

AU - Lal, Dennis

AU - Ruppert, Ann-Kathrin

AU - Trucks, Holger

AU - Schulz, Herbert

AU - de Kovel, Carolien G

AU - Kasteleijn-Nolst Trenité, Dorothée

AU - Sonsma, Anja C M

AU - Koeleman, Bobby P

AU - Lindhout, Dick

AU - Weber, Yvonne G

AU - Lerche, Holger

AU - Kapser, Claudia

AU - Schankin, Christoph J

AU - Kunz, Wolfram S

AU - Surges, Rainer

AU - Elger, Christian E

AU - Gaus, Verena

AU - Schmitz, Bettina

AU - Helbig, Ingo

AU - Muhle, Hiltrud

AU - Stephani, Ulrich

AU - Klein, Karl M

AU - Rosenow, Felix

AU - Neubauer, Bernd A

AU - Reinthaler, Eva M

AU - Zimprich, Fritz

AU - Feucht, Martha

AU - Møller, Rikke S

AU - Hjalgrim, Helle

AU - De Jonghe, Peter

AU - Suls, Arvid

AU - Lieb, Wolfgang

AU - Franke, Andre

AU - Strauch, Konstantin

AU - Gieger, Christian

AU - Schurmann, Claudia

AU - Schminke, Ulf

AU - Nürnberg, Peter

AU - Sander, Thomas

AU - EPICURE Consortium

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pgen.1005226

DO - 10.1371/journal.pgen.1005226

M3 - Journal article

C2 - 25950944

VL - 11

JO - P L o S Genetics

JF - P L o S Genetics

SN - 1553-7390

IS - 5

M1 - e1005226

ER -