Identification of new risk factors for rolandic epilepsy

CNV at Xp22.31 and alterations at cholinergic synapses

Laura Addis, William Sproviero, Sanjeev V Thomas, Roberto H Caraballo, Stephen J Newhouse, Kumudini Gomez, Elaine Hughes, Maria Kinali, David McCormick, Siobhan Hannan, Silvia Cossu, Jacqueline Taylor, Cigdem I Akman, Steven M Wolf, David E Mandelbaum, Rajesh Gupta, Rick A van der Spek, Dario Pruna, Deb K Pal

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases.

OBJECTIVE: To identify rare, causal CNV in patients with RE.

METHODS: We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India.

RESULTS: We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin.

CONCLUSION: Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.

Original languageEnglish
Pages (from-to)607-616
Number of pages10
JournalJournal of Medical Genetics
Volume55
Issue number9
DOIs
Publication statusPublished - Sep 2018
Externally publishedYes

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Rolandic Epilepsy
Synapses
Cholinergic Agents
Italy
Epilepsy
Genes
Argentina
Guanine
Sirolimus
Single Nucleotide Polymorphism
India
Seizures
Language
Mutation
Brain
Research
Population

Cite this

Addis, L., Sproviero, W., Thomas, S. V., Caraballo, R. H., Newhouse, S. J., Gomez, K., ... Pal, D. K. (2018). Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses. Journal of Medical Genetics, 55(9), 607-616. https://doi.org/10.1136/jmedgenet-2018-105319

Identification of new risk factors for rolandic epilepsy : CNV at Xp22.31 and alterations at cholinergic synapses. / Addis, Laura; Sproviero, William; Thomas, Sanjeev V; Caraballo, Roberto H; Newhouse, Stephen J; Gomez, Kumudini; Hughes, Elaine; Kinali, Maria; McCormick, David; Hannan, Siobhan; Cossu, Silvia; Taylor, Jacqueline; Akman, Cigdem I; Wolf, Steven M; Mandelbaum, David E; Gupta, Rajesh; van der Spek, Rick A; Pruna, Dario; Pal, Deb K.

In: Journal of Medical Genetics, Vol. 55, No. 9, 09.2018, p. 607-616.

Research output: Contribution to journalArticle

Addis, L, Sproviero, W, Thomas, SV, Caraballo, RH, Newhouse, SJ, Gomez, K, Hughes, E, Kinali, M, McCormick, D, Hannan, S, Cossu, S, Taylor, J, Akman, CI, Wolf, SM, Mandelbaum, DE, Gupta, R, van der Spek, RA, Pruna, D & Pal, DK 2018, 'Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses', Journal of Medical Genetics, vol. 55, no. 9, pp. 607-616. https://doi.org/10.1136/jmedgenet-2018-105319
Addis, Laura ; Sproviero, William ; Thomas, Sanjeev V ; Caraballo, Roberto H ; Newhouse, Stephen J ; Gomez, Kumudini ; Hughes, Elaine ; Kinali, Maria ; McCormick, David ; Hannan, Siobhan ; Cossu, Silvia ; Taylor, Jacqueline ; Akman, Cigdem I ; Wolf, Steven M ; Mandelbaum, David E ; Gupta, Rajesh ; van der Spek, Rick A ; Pruna, Dario ; Pal, Deb K. / Identification of new risk factors for rolandic epilepsy : CNV at Xp22.31 and alterations at cholinergic synapses. In: Journal of Medical Genetics. 2018 ; Vol. 55, No. 9. pp. 607-616.
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abstract = "BACKGROUND: Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5{\%} of cases.OBJECTIVE: To identify rare, causal CNV in patients with RE.METHODS: We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India.RESULTS: We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5{\%}) with recurrent risk factor CNVs and 15 (8.0{\%}) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin.CONCLUSION: Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.",
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TY - JOUR

T1 - Identification of new risk factors for rolandic epilepsy

T2 - CNV at Xp22.31 and alterations at cholinergic synapses

AU - Addis, Laura

AU - Sproviero, William

AU - Thomas, Sanjeev V

AU - Caraballo, Roberto H

AU - Newhouse, Stephen J

AU - Gomez, Kumudini

AU - Hughes, Elaine

AU - Kinali, Maria

AU - McCormick, David

AU - Hannan, Siobhan

AU - Cossu, Silvia

AU - Taylor, Jacqueline

AU - Akman, Cigdem I

AU - Wolf, Steven M

AU - Mandelbaum, David E

AU - Gupta, Rajesh

AU - van der Spek, Rick A

AU - Pruna, Dario

AU - Pal, Deb K

N1 - © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

PY - 2018/9

Y1 - 2018/9

N2 - BACKGROUND: Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases.OBJECTIVE: To identify rare, causal CNV in patients with RE.METHODS: We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India.RESULTS: We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin.CONCLUSION: Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.

AB - BACKGROUND: Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases.OBJECTIVE: To identify rare, causal CNV in patients with RE.METHODS: We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India.RESULTS: We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin.CONCLUSION: Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.

U2 - 10.1136/jmedgenet-2018-105319

DO - 10.1136/jmedgenet-2018-105319

M3 - Article

VL - 55

SP - 607

EP - 616

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 9

ER -