Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies.
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...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Dennis Lal [verfasserIn] Ann-Kathrin Ruppert [verfasserIn] Holger Trucks [verfasserIn] Herbert Schulz [verfasserIn] Carolien G de Kovel [verfasserIn] Dorothée Kasteleijn-Nolst Trenité [verfasserIn] Anja C M Sonsma [verfasserIn] Bobby P Koeleman [verfasserIn] Dick Lindhout [verfasserIn] Yvonne G Weber [verfasserIn] Holger Lerche [verfasserIn] Claudia Kapser [verfasserIn] Christoph J Schankin [verfasserIn] Wolfram S Kunz [verfasserIn] Rainer Surges [verfasserIn] Christian E Elger [verfasserIn] Verena Gaus [verfasserIn] Bettina Schmitz [verfasserIn] Ingo Helbig [verfasserIn] Hiltrud Muhle [verfasserIn] Ulrich Stephani [verfasserIn] Karl M Klein [verfasserIn] Felix Rosenow [verfasserIn] Bernd A Neubauer [verfasserIn] Eva M Reinthaler [verfasserIn] Fritz Zimprich [verfasserIn] Martha Feucht [verfasserIn] Rikke S Møller [verfasserIn] Helle Hjalgrim [verfasserIn] Peter De Jonghe [verfasserIn] Arvid Suls [verfasserIn] Wolfgang Lieb [verfasserIn] Andre Franke [verfasserIn] Konstantin Strauch [verfasserIn] Christian Gieger [verfasserIn] Claudia Schurmann [verfasserIn] Ulf Schminke [verfasserIn] Peter Nürnberg [verfasserIn] EPICURE Consortium [verfasserIn] Thomas Sander [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2015 |
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| Übergeordnetes Werk: |
In: PLoS Genetics - Public Library of Science (PLoS), 2005, 11(2015), 5, p e1005226 |
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| Übergeordnetes Werk: |
volume:11 ; year:2015 ; number:5, p e1005226 |
| Links: |
Link aufrufen |
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| DOI / URN: |
10.1371/journal.pgen.1005226 |
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| Katalog-ID: |
DOAJ054387809 |
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| 245 | 1 | 0 | |a Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. |
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| 520 | |a 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. | ||
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10.1371/journal.pgen.1005226 doi (DE-627)DOAJ054387809 (DE-599)DOAJ7a9aaf42fe42407c9b6b46e8e6a9130a DE-627 ger DE-627 rakwb eng QH426-470 Dennis Lal verfasserin aut Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Genetics Ann-Kathrin Ruppert verfasserin aut Holger Trucks verfasserin aut Herbert Schulz verfasserin aut Carolien G de Kovel verfasserin aut Dorothée Kasteleijn-Nolst Trenité verfasserin aut Anja C M Sonsma verfasserin aut Bobby P Koeleman verfasserin aut Dick Lindhout verfasserin aut Yvonne G Weber verfasserin aut Holger Lerche verfasserin aut Claudia Kapser verfasserin aut Christoph J Schankin verfasserin aut Wolfram S Kunz verfasserin aut Rainer Surges verfasserin aut Christian E Elger verfasserin aut Verena Gaus verfasserin aut Bettina Schmitz verfasserin aut Ingo Helbig verfasserin aut Hiltrud Muhle verfasserin aut Ulrich Stephani verfasserin aut Karl M Klein verfasserin aut Felix Rosenow verfasserin aut Bernd A Neubauer verfasserin aut Eva M Reinthaler verfasserin aut Fritz Zimprich verfasserin aut Martha Feucht verfasserin aut Rikke S Møller verfasserin aut Helle Hjalgrim verfasserin aut Peter De Jonghe verfasserin aut Arvid Suls verfasserin aut Wolfgang Lieb verfasserin aut Andre Franke verfasserin aut Konstantin Strauch verfasserin aut Christian Gieger verfasserin aut Claudia Schurmann verfasserin aut Ulf Schminke verfasserin aut Peter Nürnberg verfasserin aut EPICURE Consortium verfasserin aut Thomas Sander verfasserin aut In PLoS Genetics Public Library of Science (PLoS), 2005 11(2015), 5, p e1005226 (DE-627)485248026 (DE-600)2186725-2 15537404 nnns volume:11 year:2015 number:5, p e1005226 https://doi.org/10.1371/journal.pgen.1005226 kostenfrei https://doaj.org/article/7a9aaf42fe42407c9b6b46e8e6a9130a kostenfrei https://doi.org/10.1371/journal.pgen.1005226 kostenfrei https://doaj.org/toc/1553-7390 Journal toc kostenfrei https://doaj.org/toc/1553-7404 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2015 5, p e1005226 |
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10.1371/journal.pgen.1005226 doi (DE-627)DOAJ054387809 (DE-599)DOAJ7a9aaf42fe42407c9b6b46e8e6a9130a DE-627 ger DE-627 rakwb eng QH426-470 Dennis Lal verfasserin aut Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Genetics Ann-Kathrin Ruppert verfasserin aut Holger Trucks verfasserin aut Herbert Schulz verfasserin aut Carolien G de Kovel verfasserin aut Dorothée Kasteleijn-Nolst Trenité verfasserin aut Anja C M Sonsma verfasserin aut Bobby P Koeleman verfasserin aut Dick Lindhout verfasserin aut Yvonne G Weber verfasserin aut Holger Lerche verfasserin aut Claudia Kapser verfasserin aut Christoph J Schankin verfasserin aut Wolfram S Kunz verfasserin aut Rainer Surges verfasserin aut Christian E Elger verfasserin aut Verena Gaus verfasserin aut Bettina Schmitz verfasserin aut Ingo Helbig verfasserin aut Hiltrud Muhle verfasserin aut Ulrich Stephani verfasserin aut Karl M Klein verfasserin aut Felix Rosenow verfasserin aut Bernd A Neubauer verfasserin aut Eva M Reinthaler verfasserin aut Fritz Zimprich verfasserin aut Martha Feucht verfasserin aut Rikke S Møller verfasserin aut Helle Hjalgrim verfasserin aut Peter De Jonghe verfasserin aut Arvid Suls verfasserin aut Wolfgang Lieb verfasserin aut Andre Franke verfasserin aut Konstantin Strauch verfasserin aut Christian Gieger verfasserin aut Claudia Schurmann verfasserin aut Ulf Schminke verfasserin aut Peter Nürnberg verfasserin aut EPICURE Consortium verfasserin aut Thomas Sander verfasserin aut In PLoS Genetics Public Library of Science (PLoS), 2005 11(2015), 5, p e1005226 (DE-627)485248026 (DE-600)2186725-2 15537404 nnns volume:11 year:2015 number:5, p e1005226 https://doi.org/10.1371/journal.pgen.1005226 kostenfrei https://doaj.org/article/7a9aaf42fe42407c9b6b46e8e6a9130a kostenfrei https://doi.org/10.1371/journal.pgen.1005226 kostenfrei https://doaj.org/toc/1553-7390 Journal toc kostenfrei https://doaj.org/toc/1553-7404 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2015 5, p e1005226 |
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10.1371/journal.pgen.1005226 doi (DE-627)DOAJ054387809 (DE-599)DOAJ7a9aaf42fe42407c9b6b46e8e6a9130a DE-627 ger DE-627 rakwb eng QH426-470 Dennis Lal verfasserin aut Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Genetics Ann-Kathrin Ruppert verfasserin aut Holger Trucks verfasserin aut Herbert Schulz verfasserin aut Carolien G de Kovel verfasserin aut Dorothée Kasteleijn-Nolst Trenité verfasserin aut Anja C M Sonsma verfasserin aut Bobby P Koeleman verfasserin aut Dick Lindhout verfasserin aut Yvonne G Weber verfasserin aut Holger Lerche verfasserin aut Claudia Kapser verfasserin aut Christoph J Schankin verfasserin aut Wolfram S Kunz verfasserin aut Rainer Surges verfasserin aut Christian E Elger verfasserin aut Verena Gaus verfasserin aut Bettina Schmitz verfasserin aut Ingo Helbig verfasserin aut Hiltrud Muhle verfasserin aut Ulrich Stephani verfasserin aut Karl M Klein verfasserin aut Felix Rosenow verfasserin aut Bernd A Neubauer verfasserin aut Eva M Reinthaler verfasserin aut Fritz Zimprich verfasserin aut Martha Feucht verfasserin aut Rikke S Møller verfasserin aut Helle Hjalgrim verfasserin aut Peter De Jonghe verfasserin aut Arvid Suls verfasserin aut Wolfgang Lieb verfasserin aut Andre Franke verfasserin aut Konstantin Strauch verfasserin aut Christian Gieger verfasserin aut Claudia Schurmann verfasserin aut Ulf Schminke verfasserin aut Peter Nürnberg verfasserin aut EPICURE Consortium verfasserin aut Thomas Sander verfasserin aut In PLoS Genetics Public Library of Science (PLoS), 2005 11(2015), 5, p e1005226 (DE-627)485248026 (DE-600)2186725-2 15537404 nnns volume:11 year:2015 number:5, p e1005226 https://doi.org/10.1371/journal.pgen.1005226 kostenfrei https://doaj.org/article/7a9aaf42fe42407c9b6b46e8e6a9130a kostenfrei https://doi.org/10.1371/journal.pgen.1005226 kostenfrei https://doaj.org/toc/1553-7390 Journal toc kostenfrei https://doaj.org/toc/1553-7404 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2015 5, p e1005226 |
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10.1371/journal.pgen.1005226 doi (DE-627)DOAJ054387809 (DE-599)DOAJ7a9aaf42fe42407c9b6b46e8e6a9130a DE-627 ger DE-627 rakwb eng QH426-470 Dennis Lal verfasserin aut Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Genetics Ann-Kathrin Ruppert verfasserin aut Holger Trucks verfasserin aut Herbert Schulz verfasserin aut Carolien G de Kovel verfasserin aut Dorothée Kasteleijn-Nolst Trenité verfasserin aut Anja C M Sonsma verfasserin aut Bobby P Koeleman verfasserin aut Dick Lindhout verfasserin aut Yvonne G Weber verfasserin aut Holger Lerche verfasserin aut Claudia Kapser verfasserin aut Christoph J Schankin verfasserin aut Wolfram S Kunz verfasserin aut Rainer Surges verfasserin aut Christian E Elger verfasserin aut Verena Gaus verfasserin aut Bettina Schmitz verfasserin aut Ingo Helbig verfasserin aut Hiltrud Muhle verfasserin aut Ulrich Stephani verfasserin aut Karl M Klein verfasserin aut Felix Rosenow verfasserin aut Bernd A Neubauer verfasserin aut Eva M Reinthaler verfasserin aut Fritz Zimprich verfasserin aut Martha Feucht verfasserin aut Rikke S Møller verfasserin aut Helle Hjalgrim verfasserin aut Peter De Jonghe verfasserin aut Arvid Suls verfasserin aut Wolfgang Lieb verfasserin aut Andre Franke verfasserin aut Konstantin Strauch verfasserin aut Christian Gieger verfasserin aut Claudia Schurmann verfasserin aut Ulf Schminke verfasserin aut Peter Nürnberg verfasserin aut EPICURE Consortium verfasserin aut Thomas Sander verfasserin aut In PLoS Genetics Public Library of Science (PLoS), 2005 11(2015), 5, p e1005226 (DE-627)485248026 (DE-600)2186725-2 15537404 nnns volume:11 year:2015 number:5, p e1005226 https://doi.org/10.1371/journal.pgen.1005226 kostenfrei https://doaj.org/article/7a9aaf42fe42407c9b6b46e8e6a9130a kostenfrei https://doi.org/10.1371/journal.pgen.1005226 kostenfrei https://doaj.org/toc/1553-7390 Journal toc kostenfrei https://doaj.org/toc/1553-7404 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2015 5, p e1005226 |
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10.1371/journal.pgen.1005226 doi (DE-627)DOAJ054387809 (DE-599)DOAJ7a9aaf42fe42407c9b6b46e8e6a9130a DE-627 ger DE-627 rakwb eng QH426-470 Dennis Lal verfasserin aut Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Genetics Ann-Kathrin Ruppert verfasserin aut Holger Trucks verfasserin aut Herbert Schulz verfasserin aut Carolien G de Kovel verfasserin aut Dorothée Kasteleijn-Nolst Trenité verfasserin aut Anja C M Sonsma verfasserin aut Bobby P Koeleman verfasserin aut Dick Lindhout verfasserin aut Yvonne G Weber verfasserin aut Holger Lerche verfasserin aut Claudia Kapser verfasserin aut Christoph J Schankin verfasserin aut Wolfram S Kunz verfasserin aut Rainer Surges verfasserin aut Christian E Elger verfasserin aut Verena Gaus verfasserin aut Bettina Schmitz verfasserin aut Ingo Helbig verfasserin aut Hiltrud Muhle verfasserin aut Ulrich Stephani verfasserin aut Karl M Klein verfasserin aut Felix Rosenow verfasserin aut Bernd A Neubauer verfasserin aut Eva M Reinthaler verfasserin aut Fritz Zimprich verfasserin aut Martha Feucht verfasserin aut Rikke S Møller verfasserin aut Helle Hjalgrim verfasserin aut Peter De Jonghe verfasserin aut Arvid Suls verfasserin aut Wolfgang Lieb verfasserin aut Andre Franke verfasserin aut Konstantin Strauch verfasserin aut Christian Gieger verfasserin aut Claudia Schurmann verfasserin aut Ulf Schminke verfasserin aut Peter Nürnberg verfasserin aut EPICURE Consortium verfasserin aut Thomas Sander verfasserin aut In PLoS Genetics Public Library of Science (PLoS), 2005 11(2015), 5, p e1005226 (DE-627)485248026 (DE-600)2186725-2 15537404 nnns volume:11 year:2015 number:5, p e1005226 https://doi.org/10.1371/journal.pgen.1005226 kostenfrei https://doaj.org/article/7a9aaf42fe42407c9b6b46e8e6a9130a kostenfrei https://doi.org/10.1371/journal.pgen.1005226 kostenfrei https://doaj.org/toc/1553-7390 Journal toc kostenfrei https://doaj.org/toc/1553-7404 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2015 5, p e1005226 |
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Dennis Lal @@aut@@ Ann-Kathrin Ruppert @@aut@@ Holger Trucks @@aut@@ Herbert Schulz @@aut@@ Carolien G de Kovel @@aut@@ Dorothée Kasteleijn-Nolst Trenité @@aut@@ Anja C M Sonsma @@aut@@ Bobby P Koeleman @@aut@@ Dick Lindhout @@aut@@ Yvonne G Weber @@aut@@ Holger Lerche @@aut@@ Claudia Kapser @@aut@@ Christoph J Schankin @@aut@@ Wolfram S Kunz @@aut@@ Rainer Surges @@aut@@ Christian E Elger @@aut@@ Verena Gaus @@aut@@ Bettina Schmitz @@aut@@ Ingo Helbig @@aut@@ Hiltrud Muhle @@aut@@ Ulrich Stephani @@aut@@ Karl M Klein @@aut@@ Felix Rosenow @@aut@@ Bernd A Neubauer @@aut@@ Eva M Reinthaler @@aut@@ Fritz Zimprich @@aut@@ Martha Feucht @@aut@@ Rikke S Møller @@aut@@ Helle Hjalgrim @@aut@@ Peter De Jonghe @@aut@@ Arvid Suls @@aut@@ Wolfgang Lieb @@aut@@ Andre Franke @@aut@@ Konstantin Strauch @@aut@@ Christian Gieger @@aut@@ Claudia Schurmann @@aut@@ Ulf Schminke @@aut@@ Peter Nürnberg @@aut@@ EPICURE Consortium @@aut@@ Thomas Sander @@aut@@ |
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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.</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Genetics</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ann-Kathrin Ruppert</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Holger Trucks</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Herbert Schulz</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" 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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. |
| abstractGer |
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. |
| abstract_unstemmed |
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. |
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5, p e1005226 |
| title_short |
Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. |
| url |
https://doi.org/10.1371/journal.pgen.1005226 https://doaj.org/article/7a9aaf42fe42407c9b6b46e8e6a9130a https://doaj.org/toc/1553-7390 https://doaj.org/toc/1553-7404 |
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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 Muhle Ulrich 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 EPICURE Consortium Thomas Sander |
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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 Muhle Ulrich 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 EPICURE Consortium Thomas Sander |
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2024-07-03T22:52:18.082Z |
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| score |
7.400139 |