References of "Reid, Christopher A"
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See detailSpectrum of GABAA receptor variants in epilepsy
Maljevic, Snezana; Møller, Rikke S.; Reid, Christopher A. et al

in Current Opinion in Neurology (2019)

Purpose of review: Recent publications point to an increasingly important role of variants in genes encoding GABAA receptor subunits associated with both common and rare forms of epilepsies. The aim of ... [more ▼]

Purpose of review: Recent publications point to an increasingly important role of variants in genes encoding GABAA receptor subunits associated with both common and rare forms of epilepsies. The aim of this review is to give an overview of the current clinical phenotypes, genetic findings and pathophysiological mechanisms related to GABAA receptor variants. Recent findings: Early work showed that inherited variants in GABRG2 and GABRA1 cause relatively mild forms of monogenic epilepsies in large families. More recent studies have revealed that de novo variants in several GABAA receptor genes cause severe developmental and epileptic encephalopathies, inherited variants cause remarkably variable phenotypes within the same pedigrees ranging from asymptomatic carriers to developmental and epileptic encephalopathies, and variants in all GABAA receptor genes are enriched in common forms of epilepsy, namely rolandic epilepsy and genetic generalized epilepsy. Analyses from cellular expression systems and mouse models suggest that all variants cause a loss of GABAA receptor function resulting in GABAergic disinhibition. Summary: Genetic studies have revealed a crucial role of the GABAergic system in the underlying pathogenesis of various forms of common and rare epilepsies. Our understanding of functional consequences of GABAA receptor variants provide an opportunity to develop precision-based therapeutic strategies that are hopefully free from the side-effect burden seen with currently available GABAergic drugs. [less ▲]

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See detailRare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study
May, Patrick UL; Girard, Simon; Harrer, Merle et al

in Lancet Neurology (2018), 17(8), 699-708

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We ... [more ▼]

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. Methods For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. Findings Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41–4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05–2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02–2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors. Interpretation Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy. [less ▲]

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