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

Lookup NU author(s): Sunitha Balaraju, Dr Ana TopfORCiD, Dr Grace McMacken, Professor Robert Taylor, Professor Rita HorvathORCiD, Professor Bobby McFarlandORCiD, Professor Hanns Lochmuller



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2019, The Author(s).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.

Publication metadata

Author(s): Balaraju S, Topf A, McMacken G, Kumar VP, Pechmann A, Roper H, Vengalil S, Polavarapu K, Nashi S, Mahajan NP, Barbosa IA, Deshpande C, Taylor RW, Cossins J, Beeson D, Laurie S, Kirschner J, Horvath R, McFarland R, Atchayaram N, Lochmuller H

Publication type: Article

Publication status: Published

Journal: European Journal of Human Genetics

Year: 2019

Issue: ePub ahead of Print

Online publication date: 16/09/2019

Acceptance date: 29/08/2019

Date deposited: 04/11/2019

ISSN (print): 1018-4813

ISSN (electronic): 1476-5438

Publisher: Nature Publishing Group


DOI: 10.1038/s41431-019-0506-2

PubMed id: 31527857


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Funder referenceFunder name
109915/Z/15/ZWellcome Trust
201064/Z/16/ZWellcome Trust
Lily Foundation and the UK National Health Service Highly Specialised Service for Rare Mitochondrial Disorders
MR/N027302/1Medical Research Council (MRC)
MR/N025431/1Medical Research Council (MRC)
MRC/ESPRC Newcastle Molecular Pathology Node
Newton fund
UK NIHR Biomedical Research Centre in Age and Age Related Diseases