Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies
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...
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| creator | de Kovel, Carolien G. F. Trucks, Holger Helbig, Ingo Mefford, Heather C. Baker, Carl Leu, Costin Kluck, Christian Muhle, Hiltrud von Spiczak, Sarah Ostertag, Philipp Obermeier, Tanja Kleefuß-Lie, Ailing A. Hallmann, Kerstin Steffens, Michael Gaus, Verena Klein, Karl M. Hamer, Hajo M. Rosenow, Felix Brilstra, Eva H. Kasteleijn-Nolst Trenité, Dorothée Swinkels, Marielle E. M. Weber, Yvonne G. Unterberger, Iris Zimprich, Fritz Urak, Lydia Feucht, Martha Fuchs, Karoline Møller, Rikke S. Hjalgrim, Helle De Jonghe, Peter Suls, Arvid Rückert, Ina-Maria Wichmann, Heinz-Erich Franke, Andre Schreiber, Stefan Nürnberg, Peter Elger, Christian E. Lerche, Holger Stephani, Ulrich Koeleman, Bobby P. C. Lindhout, Dick Eichler, Evan E. Sander, Thomas |
| 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; χ2 = 26.7; 1 degree of freedom; P = 2.4 × 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 × 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 th |
| doi_str_mv | 10.1093/brain/awp262 |
| format | Article |
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F. ; Trucks, Holger ; Helbig, Ingo ; Mefford, Heather C. ; Baker, Carl ; Leu, Costin ; Kluck, Christian ; Muhle, Hiltrud ; von Spiczak, Sarah ; Ostertag, Philipp ; Obermeier, Tanja ; Kleefuß-Lie, Ailing A. ; Hallmann, Kerstin ; Steffens, Michael ; Gaus, Verena ; Klein, Karl M. ; Hamer, Hajo M. ; Rosenow, Felix ; Brilstra, Eva H. ; Kasteleijn-Nolst Trenité, Dorothée ; Swinkels, Marielle E. M. ; Weber, Yvonne G. ; Unterberger, Iris ; Zimprich, Fritz ; Urak, Lydia ; Feucht, Martha ; Fuchs, Karoline ; Møller, Rikke S. ; Hjalgrim, Helle ; De Jonghe, Peter ; Suls, Arvid ; Rückert, Ina-Maria ; Wichmann, Heinz-Erich ; Franke, Andre ; Schreiber, Stefan ; Nürnberg, Peter ; Elger, Christian E. ; Lerche, Holger ; Stephani, Ulrich ; Koeleman, Bobby P. C. ; Lindhout, Dick ; Eichler, Evan E. ; Sander, Thomas</creator><creatorcontrib>de Kovel, Carolien G. F. ; Trucks, Holger ; Helbig, Ingo ; Mefford, Heather C. ; Baker, Carl ; Leu, Costin ; Kluck, Christian ; Muhle, Hiltrud ; von Spiczak, Sarah ; Ostertag, Philipp ; Obermeier, Tanja ; Kleefuß-Lie, Ailing A. ; Hallmann, Kerstin ; Steffens, Michael ; Gaus, Verena ; Klein, Karl M. ; Hamer, Hajo M. ; Rosenow, Felix ; Brilstra, Eva H. ; Kasteleijn-Nolst Trenité, Dorothée ; Swinkels, Marielle E. M. ; Weber, Yvonne G. ; Unterberger, Iris ; Zimprich, Fritz ; Urak, Lydia ; Feucht, Martha ; Fuchs, Karoline ; Møller, Rikke S. ; Hjalgrim, Helle ; De Jonghe, Peter ; Suls, Arvid ; Rückert, Ina-Maria ; Wichmann, Heinz-Erich ; Franke, Andre ; Schreiber, Stefan ; Nürnberg, Peter ; Elger, Christian E. ; Lerche, Holger ; Stephani, Ulrich ; Koeleman, Bobby P. C. ; Lindhout, Dick ; Eichler, Evan E. ; Sander, Thomas</creatorcontrib><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; χ2 = 26.7; 1 degree of freedom; P = 2.4 × 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 × 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.</description><identifier>ISSN: 0006-8950</identifier><identifier>EISSN: 1460-2156</identifier><identifier>DOI: 10.1093/brain/awp262</identifier><identifier>PMID: 19843651</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Adolescent ; association ; Biological and medical sciences ; Child ; Child, Preschool ; Chromosome Deletion ; Chromosomes, Human, Pair 15 - genetics ; Chromosomes, Human, Pair 16 - genetics ; Cohort Studies ; Epilepsy, Generalized - etiology ; Epilepsy, Generalized - genetics ; Female ; Genetic Predisposition to Disease - genetics ; genetics ; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy ; Humans ; idiopathic generalized epilepsy ; Male ; Medical sciences ; microdeletions ; Nervous system (semeiology, syndromes) ; Neurology ; Original ; Pedigree ; Young Adult</subject><ispartof>Brain (London, England : 1878), 2010-01, Vol.133 (1), p.23-32</ispartof><rights>The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org 2009</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c580t-f7b88b753fc509623d9a180f783024039ca61b57a231fc778ededc78c93099e63</citedby><cites>FETCH-LOGICAL-c580t-f7b88b753fc509623d9a180f783024039ca61b57a231fc778ededc78c93099e63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,1578,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22292918$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19843651$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>de Kovel, Carolien G. F.</creatorcontrib><creatorcontrib>Trucks, Holger</creatorcontrib><creatorcontrib>Helbig, Ingo</creatorcontrib><creatorcontrib>Mefford, Heather C.</creatorcontrib><creatorcontrib>Baker, Carl</creatorcontrib><creatorcontrib>Leu, Costin</creatorcontrib><creatorcontrib>Kluck, Christian</creatorcontrib><creatorcontrib>Muhle, Hiltrud</creatorcontrib><creatorcontrib>von Spiczak, Sarah</creatorcontrib><creatorcontrib>Ostertag, Philipp</creatorcontrib><creatorcontrib>Obermeier, Tanja</creatorcontrib><creatorcontrib>Kleefuß-Lie, Ailing A.</creatorcontrib><creatorcontrib>Hallmann, Kerstin</creatorcontrib><creatorcontrib>Steffens, Michael</creatorcontrib><creatorcontrib>Gaus, Verena</creatorcontrib><creatorcontrib>Klein, Karl M.</creatorcontrib><creatorcontrib>Hamer, Hajo M.</creatorcontrib><creatorcontrib>Rosenow, Felix</creatorcontrib><creatorcontrib>Brilstra, Eva H.</creatorcontrib><creatorcontrib>Kasteleijn-Nolst Trenité, Dorothée</creatorcontrib><creatorcontrib>Swinkels, Marielle E. M.</creatorcontrib><creatorcontrib>Weber, Yvonne G.</creatorcontrib><creatorcontrib>Unterberger, Iris</creatorcontrib><creatorcontrib>Zimprich, Fritz</creatorcontrib><creatorcontrib>Urak, Lydia</creatorcontrib><creatorcontrib>Feucht, Martha</creatorcontrib><creatorcontrib>Fuchs, Karoline</creatorcontrib><creatorcontrib>Møller, Rikke S.</creatorcontrib><creatorcontrib>Hjalgrim, Helle</creatorcontrib><creatorcontrib>De Jonghe, Peter</creatorcontrib><creatorcontrib>Suls, Arvid</creatorcontrib><creatorcontrib>Rückert, Ina-Maria</creatorcontrib><creatorcontrib>Wichmann, Heinz-Erich</creatorcontrib><creatorcontrib>Franke, Andre</creatorcontrib><creatorcontrib>Schreiber, Stefan</creatorcontrib><creatorcontrib>Nürnberg, Peter</creatorcontrib><creatorcontrib>Elger, Christian E.</creatorcontrib><creatorcontrib>Lerche, Holger</creatorcontrib><creatorcontrib>Stephani, Ulrich</creatorcontrib><creatorcontrib>Koeleman, Bobby P. C.</creatorcontrib><creatorcontrib>Lindhout, Dick</creatorcontrib><creatorcontrib>Eichler, Evan E.</creatorcontrib><creatorcontrib>Sander, Thomas</creatorcontrib><title>Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies</title><title>Brain (London, England : 1878)</title><addtitle>Brain</addtitle><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; χ2 = 26.7; 1 degree of freedom; P = 2.4 × 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 × 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.</description><subject>Adolescent</subject><subject>association</subject><subject>Biological and medical sciences</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Chromosome Deletion</subject><subject>Chromosomes, Human, Pair 15 - genetics</subject><subject>Chromosomes, Human, Pair 16 - genetics</subject><subject>Cohort Studies</subject><subject>Epilepsy, Generalized - etiology</subject><subject>Epilepsy, Generalized - genetics</subject><subject>Female</subject><subject>Genetic Predisposition to Disease - genetics</subject><subject>genetics</subject><subject>Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy</subject><subject>Humans</subject><subject>idiopathic generalized epilepsy</subject><subject>Male</subject><subject>Medical sciences</subject><subject>microdeletions</subject><subject>Nervous system (semeiology, syndromes)</subject><subject>Neurology</subject><subject>Original</subject><subject>Pedigree</subject><subject>Young Adult</subject><issn>0006-8950</issn><issn>1460-2156</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0U1v1DAQBuAIgei2cOOMcoFeyNZjx459QUIVsEiLkApIFRfjOJPWkI1dO-Hr12PIaoETJx_m0cx43qJ4AGQNRLGzNho3npmvgQp6q1hBLUhFgYvbxYoQIiqpODkqjlP6RAjUjIq7xREoWTPBYVV8vEA7x4jjVO6cjb7DASfnx1SaqQR-A7CmpRm7EkQAtgYoQ8TOpeATlpMvXed8MNO1s-UVjhjN4H5gV2JwA4bkMN0r7vRmSHh__54U7188f3e-qbZvXr46f7atLJdkqvqmlbJtOOstJ0pQ1ikDkvSNZITWhClrBLS8MZRBb5tGYoedbaRVjCiFgp0UT5e-YW53uZR_lJfRIbqdid-1N07_Wxndtb7yXzSVBBhlucHjfYPob2ZMk965ZHEYzIh-TppCniQ5z_DJAvO5UorYH4YA0b8i0b8j0UskmT_8e7E_eJ9BBo_2wCRrhj6a0bp0cJRSRRXI7E4X5-fwv5HVIl2a8NvBmvhZi4Y1XG8uP-iL1xtRv70EvWU_AdAHssE</recordid><startdate>20100101</startdate><enddate>20100101</enddate><creator>de Kovel, Carolien G. F.</creator><creator>Trucks, Holger</creator><creator>Helbig, Ingo</creator><creator>Mefford, Heather C.</creator><creator>Baker, Carl</creator><creator>Leu, Costin</creator><creator>Kluck, Christian</creator><creator>Muhle, Hiltrud</creator><creator>von Spiczak, Sarah</creator><creator>Ostertag, Philipp</creator><creator>Obermeier, Tanja</creator><creator>Kleefuß-Lie, Ailing A.</creator><creator>Hallmann, Kerstin</creator><creator>Steffens, Michael</creator><creator>Gaus, Verena</creator><creator>Klein, Karl M.</creator><creator>Hamer, Hajo M.</creator><creator>Rosenow, Felix</creator><creator>Brilstra, Eva H.</creator><creator>Kasteleijn-Nolst Trenité, Dorothée</creator><creator>Swinkels, Marielle E. M.</creator><creator>Weber, Yvonne G.</creator><creator>Unterberger, Iris</creator><creator>Zimprich, Fritz</creator><creator>Urak, Lydia</creator><creator>Feucht, Martha</creator><creator>Fuchs, Karoline</creator><creator>Møller, Rikke S.</creator><creator>Hjalgrim, Helle</creator><creator>De Jonghe, Peter</creator><creator>Suls, Arvid</creator><creator>Rückert, Ina-Maria</creator><creator>Wichmann, Heinz-Erich</creator><creator>Franke, Andre</creator><creator>Schreiber, Stefan</creator><creator>Nürnberg, Peter</creator><creator>Elger, Christian E.</creator><creator>Lerche, Holger</creator><creator>Stephani, Ulrich</creator><creator>Koeleman, Bobby P. C.</creator><creator>Lindhout, Dick</creator><creator>Eichler, Evan E.</creator><creator>Sander, Thomas</creator><general>Oxford University Press</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>5PM</scope></search><sort><creationdate>20100101</creationdate><title>Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies</title><author>de Kovel, Carolien G. F. ; Trucks, Holger ; Helbig, Ingo ; Mefford, Heather C. ; Baker, Carl ; Leu, Costin ; Kluck, Christian ; Muhle, Hiltrud ; von Spiczak, Sarah ; Ostertag, Philipp ; Obermeier, Tanja ; Kleefuß-Lie, Ailing A. ; Hallmann, Kerstin ; Steffens, Michael ; Gaus, Verena ; Klein, Karl M. ; Hamer, Hajo M. ; Rosenow, Felix ; Brilstra, Eva H. ; Kasteleijn-Nolst Trenité, Dorothée ; Swinkels, Marielle E. M. ; Weber, Yvonne G. ; Unterberger, Iris ; Zimprich, Fritz ; Urak, Lydia ; Feucht, Martha ; Fuchs, Karoline ; Møller, Rikke S. ; Hjalgrim, Helle ; De Jonghe, Peter ; Suls, Arvid ; Rückert, Ina-Maria ; Wichmann, Heinz-Erich ; Franke, Andre ; Schreiber, Stefan ; Nürnberg, Peter ; Elger, Christian E. ; Lerche, Holger ; Stephani, Ulrich ; Koeleman, Bobby P. C. ; Lindhout, Dick ; Eichler, Evan E. ; Sander, Thomas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c580t-f7b88b753fc509623d9a180f783024039ca61b57a231fc778ededc78c93099e63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adolescent</topic><topic>association</topic><topic>Biological and medical sciences</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Chromosome Deletion</topic><topic>Chromosomes, Human, Pair 15 - genetics</topic><topic>Chromosomes, Human, Pair 16 - genetics</topic><topic>Cohort Studies</topic><topic>Epilepsy, Generalized - etiology</topic><topic>Epilepsy, Generalized - genetics</topic><topic>Female</topic><topic>Genetic Predisposition to Disease - genetics</topic><topic>genetics</topic><topic>Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy</topic><topic>Humans</topic><topic>idiopathic generalized epilepsy</topic><topic>Male</topic><topic>Medical sciences</topic><topic>microdeletions</topic><topic>Nervous system (semeiology, syndromes)</topic><topic>Neurology</topic><topic>Original</topic><topic>Pedigree</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>de Kovel, Carolien G. F.</creatorcontrib><creatorcontrib>Trucks, Holger</creatorcontrib><creatorcontrib>Helbig, Ingo</creatorcontrib><creatorcontrib>Mefford, Heather C.</creatorcontrib><creatorcontrib>Baker, Carl</creatorcontrib><creatorcontrib>Leu, Costin</creatorcontrib><creatorcontrib>Kluck, Christian</creatorcontrib><creatorcontrib>Muhle, Hiltrud</creatorcontrib><creatorcontrib>von Spiczak, Sarah</creatorcontrib><creatorcontrib>Ostertag, Philipp</creatorcontrib><creatorcontrib>Obermeier, Tanja</creatorcontrib><creatorcontrib>Kleefuß-Lie, Ailing A.</creatorcontrib><creatorcontrib>Hallmann, Kerstin</creatorcontrib><creatorcontrib>Steffens, Michael</creatorcontrib><creatorcontrib>Gaus, Verena</creatorcontrib><creatorcontrib>Klein, Karl M.</creatorcontrib><creatorcontrib>Hamer, Hajo M.</creatorcontrib><creatorcontrib>Rosenow, Felix</creatorcontrib><creatorcontrib>Brilstra, Eva H.</creatorcontrib><creatorcontrib>Kasteleijn-Nolst Trenité, Dorothée</creatorcontrib><creatorcontrib>Swinkels, Marielle E. M.</creatorcontrib><creatorcontrib>Weber, Yvonne G.</creatorcontrib><creatorcontrib>Unterberger, Iris</creatorcontrib><creatorcontrib>Zimprich, Fritz</creatorcontrib><creatorcontrib>Urak, Lydia</creatorcontrib><creatorcontrib>Feucht, Martha</creatorcontrib><creatorcontrib>Fuchs, Karoline</creatorcontrib><creatorcontrib>Møller, Rikke S.</creatorcontrib><creatorcontrib>Hjalgrim, Helle</creatorcontrib><creatorcontrib>De Jonghe, Peter</creatorcontrib><creatorcontrib>Suls, Arvid</creatorcontrib><creatorcontrib>Rückert, Ina-Maria</creatorcontrib><creatorcontrib>Wichmann, Heinz-Erich</creatorcontrib><creatorcontrib>Franke, Andre</creatorcontrib><creatorcontrib>Schreiber, Stefan</creatorcontrib><creatorcontrib>Nürnberg, Peter</creatorcontrib><creatorcontrib>Elger, Christian E.</creatorcontrib><creatorcontrib>Lerche, Holger</creatorcontrib><creatorcontrib>Stephani, Ulrich</creatorcontrib><creatorcontrib>Koeleman, Bobby P. C.</creatorcontrib><creatorcontrib>Lindhout, Dick</creatorcontrib><creatorcontrib>Eichler, Evan E.</creatorcontrib><creatorcontrib>Sander, Thomas</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Brain (London, England : 1878)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>de Kovel, Carolien G. F.</au><au>Trucks, Holger</au><au>Helbig, Ingo</au><au>Mefford, Heather C.</au><au>Baker, Carl</au><au>Leu, Costin</au><au>Kluck, Christian</au><au>Muhle, Hiltrud</au><au>von Spiczak, Sarah</au><au>Ostertag, Philipp</au><au>Obermeier, Tanja</au><au>Kleefuß-Lie, Ailing A.</au><au>Hallmann, Kerstin</au><au>Steffens, Michael</au><au>Gaus, Verena</au><au>Klein, Karl M.</au><au>Hamer, Hajo M.</au><au>Rosenow, Felix</au><au>Brilstra, Eva H.</au><au>Kasteleijn-Nolst Trenité, Dorothée</au><au>Swinkels, Marielle E. M.</au><au>Weber, Yvonne G.</au><au>Unterberger, Iris</au><au>Zimprich, Fritz</au><au>Urak, Lydia</au><au>Feucht, Martha</au><au>Fuchs, Karoline</au><au>Møller, Rikke S.</au><au>Hjalgrim, Helle</au><au>De Jonghe, Peter</au><au>Suls, Arvid</au><au>Rückert, Ina-Maria</au><au>Wichmann, Heinz-Erich</au><au>Franke, Andre</au><au>Schreiber, Stefan</au><au>Nürnberg, Peter</au><au>Elger, Christian E.</au><au>Lerche, Holger</au><au>Stephani, Ulrich</au><au>Koeleman, Bobby P. C.</au><au>Lindhout, Dick</au><au>Eichler, Evan E.</au><au>Sander, Thomas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies</atitle><jtitle>Brain (London, England : 1878)</jtitle><addtitle>Brain</addtitle><date>2010-01-01</date><risdate>2010</risdate><volume>133</volume><issue>1</issue><spage>23</spage><epage>32</epage><pages>23-32</pages><issn>0006-8950</issn><eissn>1460-2156</eissn><abstract>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; χ2 = 26.7; 1 degree of freedom; P = 2.4 × 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 × 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.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>19843651</pmid><doi>10.1093/brain/awp262</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0006-8950 |
| ispartof | Brain (London, England : 1878), 2010-01, Vol.133 (1), p.23-32 |
| issn | 0006-8950 1460-2156 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2801323 |
| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adolescent association Biological and medical sciences Child Child, Preschool Chromosome Deletion Chromosomes, Human, Pair 15 - genetics Chromosomes, Human, Pair 16 - genetics Cohort Studies Epilepsy, Generalized - etiology Epilepsy, Generalized - genetics Female Genetic Predisposition to Disease - genetics genetics Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy Humans idiopathic generalized epilepsy Male Medical sciences microdeletions Nervous system (semeiology, syndromes) Neurology Original Pedigree Young Adult |
| title | Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies |
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