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 - Publisher Copyright:
© 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 - 2018/9/1
Y1 - 2018/9/1
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
C2 - 29789371
AN - SCOPUS:85048024876
SN - 0022-2593
VL - 55
SP - 607
EP - 616
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 9
ER -