Biallelic Mutations in SLC1A2; an Additional Mode of Inheritance for SLC1A2-Related Epilepsy

Abstract

Recently, heterozygous de novo mutations in have been reported to underlie severe early-onset epileptic encephalopathy. In one male presenting with epileptic seizures and visual impairment, we identified a novel homozygous splicing variant in (c.1421 + 1G > C) by using exome sequencing. Functional studies on cDNA level confirmed a consecutive loss of function. Our findings suggest that not only de novo mutations but also biallelic variants in can cause epilepsy and that there is an additional autosomal recessive mode of inheritance. These findings also contribute to the understanding of the genetic mechanism of autosomal dominant-related epileptic encephalopathy as they exclude haploinsufficiency as exclusive genetic mechanism.

Loss of glutamate transporter eaat2a leads to aberrant neuronal excitability, recurrent epileptic seizures, and basal hypoactivity

“…In this study, we show that a genetic perturbation of the excitatory glutamate system leads to profound functional alterations in neuronal and astroglial networks, leading to spontaneous and light-induced seizures. Our results are in line with the earlier observations associating EAAT2 malfunctions to seizures in mice and humans (Epi4K Consortium et al, 2013;Epi4K Consortium, 2016;Guella et al, 2017;Petr et al, 2015;Stergachis et al, 2019;Tanaka et al, 1997;Wagner et al, 2018), and with findings on abnormal motor behavior in the zebrafish techno trousers (tnt) mutant defective in EAAT2a (McKeown et al, 2012). Firstly, homozygous mutations of the astroglial eaat2a in zebrafish resemble a form of DEE present in human epilepsy patients with de novo mutations in the orthologous gene (EAAT2 = SLC1A2) (Epi4K Consortium et al, 2013;Epi4K Consortium, 2016;Guella et al, 2017).…”

Genes4Epilepsy: An epilepsy gene resource

“…In the case of the latter group, this may be the result of different variant effects. For example, recessive disease might result from two loss of function variants, whereas dominant disease may result from a single gain of function variant in the same gene 11–13 …”

“…For example, recessive disease might result from two loss of function variants, whereas dominant disease may result from a single gain of function variant in the same gene. 11 , 12 , 13 …”

“…For example, recessive disease might result from two loss of function variants, whereas dominant disease may result from a single gain of function variant in the same gene. [11][12][13] Almost 90% of the curated monogenic genes have been associated with a DEE phenotype (n = 825/926 total). By comparison, just 5% of all epilepsy genes were associated with a GGE and/or focal epilepsy phenotype (n = 45/926).…”

Results From the WAGR Syndrome Patient Registry: Characterization of WAGR Spectrum and Recommendations for Care Management

“…Patients with WAGR may have undiagnosed epilepsy or unrecognized seizures, as a patient affected by WAGR with obesity was described with signs of rolandic epilepsy of childhood demonstrated by electroencephalogram, despite the absence of seizures ( 59 ). Further research is needed to explore potential mechanisms leading to seizures in patients with WAGR syndrome, as a variety involving the common WAGR genes and SLC1A2 and ELP4 genes have been suggested ( 24 , 60 , 61 ).…”