RT Journal Article
SR Electronic
T1 Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP jmedgenet-2018-105319
DO 10.1136/jmedgenet-2018-105319
A1 Laura Addis
A1 William Sproviero
A1 Sanjeev V Thomas
A1 Roberto H Caraballo
A1 Stephen J Newhouse
A1 Kumudini Gomez
A1 Elaine Hughes
A1 Maria Kinali
A1 David McCormick
A1 Siobhan Hannan
A1 Silvia Cossu
A1 Jacqueline Taylor
A1 Cigdem I Akman
A1 Steven M Wolf
A1 David E Mandelbaum
A1 Rajesh Gupta
A1 Rick A van der Spek
A1 Dario Pruna
A1 Deb K Pal
YR 2018
UL http://jmg.bmj.com/content/early/2018/05/22/jmedgenet-2018-105319.abstract
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.