Defining the phenotypic spectrum of <i>SLC6A1</i> mutations

Johannesen, Katrine M; Gardella, Elena; Linnankivi, Tarja; Courage, Carolina; Saint‐Martin, Anne de; Lehesjoki, Anna Elina; Mignot, Cyril; Afenjar, Alexandra; Lesca, Gaëtan; Abi-Warde, Marie Thérèse; Chelly, Jamel; Piton, Amélie; Merritt, J. Lawrence; Rodan, Lance H.; Tan, Wen; Bird, Lynne M.; Nespeca, Mark; Gleeson, Joseph G.; Yoo, Yongjin; Choi, Murim; Chae, Jong Hee; Czapansky-Beilman, Desiree; Reichert, Sara Chadwick; Pendziwiat, Manuela; Verhoeven, Judith; Schelhaas, Helenius J.; Devinsky, Orrin; Christensen, Jakob; Specchio, Nicola; Trivisano, Marina; Weber, Yvonne G.; Nava, Caroline; Keren, Boris; Doummar, Diane; Schaefer, Eric; Hopkins, Sarah; Dubbs, Holly; Shaw, Jessica E.; Pisani, Laura Rosa; Myers, Candace T.; Tang, Sha; Tang, Shan; Pal, Deb K.; Millichap, J; Carvill, Gemma L.; Helbig, Kathrine L.; Mecarelli, Oriano; Striano, Pasquale; Helbig, Ingo; Rubboli, Guido; Mefford, Heather C; Møller, Rikke S.

doi:10.1111/epi.13986

Cited by 107 publications

(159 citation statements)

References 19 publications

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“…Coincidentally, two of the patients in the current study were included in a recent publication by Johannesen et al. Specifically, Patient 3 (p.F270S) and Patient 5 (c.850‐2A>G) correspond to Patient 10 and Patient 32, respectively, in the study by Johannesen et al …”

Section: Resultsmentioning

confidence: 87%

“…Stars indicate approximate locations of the eight variants identified in the present study. Circles indicate previously published missense (dark blue) and in‐frame deletion (pink) variants, and truncating variants are indicated by triangles: nonsense (red), frameshift (light blue), and splice‐site (orange) . Variant positions are based on the previously published LeuT crystal structure .…”

Section: Resultsmentioning

confidence: 99%

“…Variants in SLC6A1 were first identified in patients presenting with myoclonic‐atonic epilepsy, which is characterized by a range of seizure types including myoclonic, myoclonic‐atonic, atonic, and absence seizures. Additionally, patients with myoclonic‐atonic epilepsy also have variable degrees of intellectual disability, developmental delay, and in some cases, autism spectrum disorder, and other behavioral disorders . Recently, Johannesen et al showed that variants in SLC6A1 are more broadly associated with generalized epilepsies, with absence seizures and intellectual disability being common phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, patients with myoclonic‐atonic epilepsy also have variable degrees of intellectual disability, developmental delay, and in some cases, autism spectrum disorder, and other behavioral disorders . Recently, Johannesen et al showed that variants in SLC6A1 are more broadly associated with generalized epilepsies, with absence seizures and intellectual disability being common phenotypes. In the present study, we identified eight SLC6A1 variants in individuals with epilepsy and evaluated their functional effects.…”

Section: Discussionmentioning

confidence: 99%

“…SLC6A1 encodes the electrogenic sodium and chloride‐coupled γ‐aminobutyric acid (GABA) transporter, GAT‐1, which is responsible for the reuptake of the inhibitory neurotransmitter GABA from the synapse . Previous reports identified heterozygous SLC6A1 variants in patients with myoclonic‐atonic epilepsy (also called myoclonic‐astatic epilepsy or Doose syndrome) and other generalized epilepsies . Although it has been hypothesized that SLC6A1 epilepsy mutations are likely to be loss‐of‐function, the functional effects of these reported variants have not yet been experimentally determined.…”

Section: Introductionmentioning

confidence: 99%

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SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

et al. 2018

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Previous reports have identified SLC6A1 variants in patients with generalized epilepsies, such as myoclonic-atonic epilepsy and childhood absence epilepsy. However, to date, none of the identified SLC6A1 variants has been functionally tested for an effect on GAT-1 transporter activity. The purpose of this study was to determine the incidence of SLC6A1 variants in 460 unselected epilepsy patients and to evaluate the impact of the identified variants on γ-aminobutyric acid (GABA)transport. Targeted resequencing was used to screen 460 unselected epilepsy patients for variants in SLC6A1. Five missense variants, one in-frame deletion, one nonsense variant, and one intronic splice-site variant were identified, representing a 1.7% diagnostic yield. Using a [ H]-GABA transport assay, the seven identified exonic variants were found to reduce GABA transport activity. A minigene splicing assay revealed that the splice-site variant disrupted canonical splicing of exon 9 in the mRNA transcript, leading to premature protein truncation. These findings demonstrate that SLC6A1 is an important contributor to childhood epilepsy and that reduced GAT-1 function is a common consequence of epilepsy-causing SLC6A1 variants.

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Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

et al. 2018

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NBEA: Developmental disease gene with early generalized epilepsy phenotypes

Mulhern¹,

Stumpel²,

Stong³

et al. 2018

Annals of Neurology

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NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a Myoclonic-Astatic Epilepsy (MAE)-like phenotype in a subset of patients.

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De novo absence status epilepticus associated with the SLC6A1 gene in a pediatric patient

Caraballo,

Chacón,

Touzon

et al. 2023

Epileptic Disorders

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Defining the phenotypic spectrum of SLC6A1 mutations

Abstract: Most patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.

Cited by 107 publications

References 19 publications

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

NBEA: Developmental disease gene with early generalized epilepsy phenotypes

De novo absence status epilepticus associated with the SLC6A1 gene in a pediatric patient

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