King's College London

Research portal

Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses

Research output: Contribution to journalArticle

Standard

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.

Research output: Contribution to journalArticle

Harvard

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. https://doi.org/10.1136/jmedgenet-2018-105319

APA

Addis, L., Sproviero, W., Thomas, S. V., Caraballo, R. H., Newhouse, S. J., Gomez, K., Hughes, E., Kinali, M., McCormick, D., Hannan, S., Cossu, S., Taylor, J., Akman, C. I., Wolf, S. M., Mandelbaum, D. E., Gupta, R., Van Der Spek, R. A., Pruna, D., & 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). https://doi.org/10.1136/jmedgenet-2018-105319

Vancouver

Addis L, Sproviero W, Thomas SV, Caraballo RH, Newhouse SJ, Gomez K et al. Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses. Journal of Medical Genetics. 2018 Sep;55(9). https://doi.org/10.1136/jmedgenet-2018-105319

Author

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.

Bibtex Download

@article{395db7d75dc146a5aa1b196cf5852821,
title = "Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses",
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.",
keywords = "copy-number, developmental, epilepsy and seizures, genome-wide",
author = "Laura Addis and William Sproviero and Thomas, {Sanjeev V.} and Caraballo, {Roberto H.} and Newhouse, {Stephen J.} and Kumudini Gomez and Elaine Hughes and Maria Kinali and David McCormick and Siobhan Hannan and Silvia Cossu and Jacqueline Taylor and Akman, {Cigdem I.} and Wolf, {Steven M.} and Mandelbaum, {David E.} and Rajesh Gupta and {Van Der Spek}, {Rick A.} and Dario Pruna and Pal, {Deb K.}",
year = "2018",
month = sep,
doi = "10.1136/jmedgenet-2018-105319",
language = "English",
volume = "55",
journal = "J Med Genet",
issn = "0022-2593",
publisher = "B M J PUBLISHING GROUP",
number = "9",

}

RIS (suitable for import to EndNote) Download

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.

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.

KW - copy-number

KW - developmental

KW - epilepsy and seizures

KW - genome-wide

UR - http://www.scopus.com/inward/record.url?scp=85048024876&partnerID=8YFLogxK

U2 - 10.1136/jmedgenet-2018-105319

DO - 10.1136/jmedgenet-2018-105319

M3 - Article

AN - SCOPUS:85048024876

VL - 55

JO - J Med Genet

JF - J Med Genet

SN - 0022-2593

IS - 9

ER -

View graph of relations

© 2018 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454