Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant

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• dc.contributor.author Lochmüller, Hanns
• dc.contributor.author Balaraju, Sunitha
• dc.contributor.author Laurie, Steven, 1973-
• dc.contributor.author Lochmüller, Hanns
• dc.date.accessioned 2020-03-19T10:08:15Z
• dc.date.available 2020-03-19T10:08:15Z
• dc.date.issued 2020
• dc.description.abstract Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of disorders caused by mutations which lead to impaired neuromuscular transmission. SLC25A1 encodes a mitochondrial citrate carrier, associated mainly with the severe neurometabolic disease combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). We previously reported a single family with a homozygous missense variant in SLC25A1 with a phenotype restricted to relatively mild CMS with intellectual disability, but to date no additional cases of this CMS subtype had been reported. Here, we performed whole exome sequencing (WES) in three additional and unrelated families presenting with CMS and mild intellectual disability to identify the underlying causative gene. The WES analysis revealed the presence of a homozygous c.740G>A; p.(Arg247Gln) missense SLC25A1 variant, the same SLC25A1 variant as identified in the original family with this phenotype. Electron microscopy of muscle from two cases revealed enlarged and accumulated mitochondria. Haplotype analysis performed in two unrelated families suggested that this variant is a result of recurrent mutation and not a founder effect. This suggests that p.(Arg247Gln) is associated with a relatively mild CMS phenotype with subtle mitochondrial abnormalities, while other variants in this gene cause more severe neurometabolic disease. In conclusion, the p.(Arg247Gln) SLC25A1 variant should be considered in patients presenting with a presynaptic CMS phenotype, particularly with accompanying intellectual disability.
• dc.description.sponsorship The project is supported by Newton fund under the governance of Academy of Medical Sciences. SB is a Newton International postdoctoral fellow (Ref no.NIF003/1002). RH was supported by the Medical Research Council (UK) [MR/N025431/1], the Wellcome Investigator fund [109915/Z/15/Z], the Newton Fund [UK/Turkey, MR/N027302/1], the European Research Council [309548] and the Wellcome Trust Pathfinder Scheme [201064/Z/16/Z]. RM and RWT are supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the MRC Centre for Neuromuscular Diseases (G0601943), Newcastle University Centre for Ageing and Vitality (supported by the Biotechnology and Biological Sciences Research Council and Medical Research Council (G016354/1). HL is supported by a project grant of the Canadian Institutes of Health Research (CIHR, PJT 162265)
• dc.format.mimetype application/pdf
• dc.identifier.citation Balaraju S, Töpf A, McMacken G, Kumar VP, Pechmann A, Roper H et al. Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant. Eur J Hum Genet. 2020 Mar; 28(3): 373-377. DOI: 10.1038/s41431-019-0506-2
• dc.identifier.doi http://dx.doi.org/10.1038/s41431-019-0506-2
• dc.identifier.issn 1018-4813
• dc.identifier.uri http://hdl.handle.net/10230/43951
• dc.language.iso eng
• dc.publisher Springer
• dc.relation.ispartof European Journal of Human Genetics. 2020 Mar; 28(3): 373-7
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309548
• dc.rights © 2019 Sunitha Balaraju et al. This article is published with open access
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.other Malalties congènites
• dc.subject.other Malalties neuromusculars
• dc.title Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion