期刊
EUROPEAN JOURNAL OF HUMAN GENETICS
卷 28, 期 3, 页码 373-377出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41431-019-0506-2
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资金
- Newton fund under the governance of Academy of Medical Sciences
- Medical Research Council (UK) [MR/N025431/1]
- Wellcome Investigator fund [109915/Z/15/Z]
- Newton Fund [UK/Turkey] [MR/N027302/1]
- European Research Council [309548]
- Wellcome Trust Pathfinder Scheme [201064/Z/16/Z]
- Wellcome Centre for Mitochondrial Research [203105/Z/16/Z]
- MRC Centre for Neuromuscular Diseases [G0601943]
- Newcastle University Centre for Ageing and Vitality - Biotechnology and Biological Sciences Research Council [G016354/1]
- Newcastle University Centre for Ageing and Vitality - Medical Research Council [G016354/1]
- UK NIHR Biomedical Research Centre in Age and Age Related Diseases
- MRC/ESPRC Newcastle Molecular Pathology Node
- Lily Foundation
- UK National Health Service Highly Specialised Service for Rare Mitochondrial Disorders
- Canadian Institutes of Health Research (CIHR) [PJT 162265]
- MRC [MR/N025431/1, G0601943, MR/N010035/1, MR/M006824/1, G1000848, MR/N025431/2] Funding Source: UKRI
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.
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