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

doi:10.1136/jmedgenet-2018-105319

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

^*Corresponding author for this work

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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.

Original language	English
Journal	Journal of Medical Genetics
Volume	55
Issue number	9
Early online date	22 May 2018
DOIs	https://doi.org/10.1136/jmedgenet-2018-105319
Publication status	Published - Sept 2018

Keywords

copy-number
developmental
epilepsy and seizures
genome-wide

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10.1136/jmedgenet-2018-105319Licence: CC BY

Identification of new risk_ADDIS_Accepted28April2018_GOLD VoR (CC BY)Final published version, 1.25 MBLicence: CC BY

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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

@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 = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "B M J PUBLISHING GROUP",

number = "9",

}

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

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

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U2 - 10.1136/jmedgenet-2018-105319

DO - 10.1136/jmedgenet-2018-105319

M3 - Article

AN - SCOPUS:85048024876

SN - 0022-2593

VL - 55

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 9

ER -

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

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