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

TitleCongenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant.
Publication TypeJournal Article
Year of Publication2020
AuthorsBalaraju, S, Topf, A, McMacken, G, Kumar, VPreethish, Pechmann, A, Roper, H, Vengalil, S, Polavarapu, K, Nashi, S, Mahajan, NPrakash, Barbosa, IA, Deshpande, C, Taylor, RW, Cossins, J, Beeson, D, Laurie, S, Kirschner, J, Horvath, R, McFarland, R, Nalini, A, Lochmüller, H
JournalEur J Hum Genet
Volume28
Issue3
Pagination373-377
Date Published2020 Mar
ISSN1476-5438
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.

DOI10.1038/s41431-019-0506-2
Alternate JournalEur. J. Hum. Genet.
PubMed ID31527857
PubMed Central IDPMC7029005
Grant List / WT / Wellcome Trust / United Kingdom
MR/M006824/1 / MR / Medical Research Council / United Kingdom
UM1 HG008900 / HG / NHGRI NIH HHS / United States
NIF003/1002 / AM / Academy of Medical Sciences / United Kingdom