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Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies.

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BACKGROUND: Peripheral neuropathies in mitochondrial disease are caused by mutations in nuclear genes encoding mitochondrial proteins, or in the mitochondrial genome. Whole exome or genome sequencing enable parallel testing of nuclear and mtDNA genes, and it has significantly advanced the genetic diagnosis of inherited diseases. Despite this, approximately 40% of all Charcot-Marie-Tooth (CMT) cases remain undiagnosed. METHODS: The genome-phenome analysis platform (GPAP) in RD-Connect was utilised to create a cohort of 2087 patients with at least one Human Phenotype Ontology (HPO) term suggestive of a peripheral neuropathy, from a total of 10,935 patients. These patients' genetic data were then analysed and searched for variants in known mitochondrial disease genes. RESULTS: A total of 1,379 rare variants were identified, 44 of which were included in this study as either reported pathogenic or likely causative in 42 patients from 36 families. The most common genes found to be likely causative for an autosomal dominant neuropathy were GDAP1 and GARS1. We also detected heterozygous likely pathogenic variants in DNA2, MFN2, DNM2, PDHA1, SDHA, and UCHL1. Biallelic variants in SACS, SPG7, GDAP1, C12orf65, UCHL1, NDUFS6, ETFDH and DARS2 and variants in the mitochondrial DNA (mtDNA)-encoded MT-ATP6 and MT-TK were also causative for mitochondrial CMT. Only 50% of these variants were already reported as solved in GPAP. CONCLUSION: Variants in mitochondrial disease genes are frequent in patients with inherited peripheral neuropathies. Due to the clinical overlap between mitochondrial disease and CMT, agnostic exome or genome sequencing have better diagnostic yields than targeted gene panels.


Acknowledgements: T.F. received support from Queens’ College, University of Cambridge, the Wolfson Foundation, and the Royal College of Physicians. R.H. is a Wellcome Trust Investigator (109915/Z/15/Z, and 226653/Z/22/Z), who receives support from the Medical Research Council (UK) (MR/V009346/1), the Addenbrooke’s Charitable Trust (G100142), the Evelyn Trust, the Stoneygate Trust, the Lily Foundation, Action for AT, Muscular Dystrophy UK, and an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. This study was further supported by the Horizon 2020 research and innovation programme via grant 779257 “Solve-RD”. Data were analysed using the RD-Connect Genome-Phenome Analysis Platform developed under FP7/2007-2013 funded project (grant agreement nº 305444) and funding from European Joint Programme in Rare Disease (EJP-RD) and INB/ELIXIR-ES. HL receives support from the Canadian Institutes of Health Research (CIHR) for Foundation Grant FDN-167281 (Precision Health for Neuromuscular Diseases), Transnational Team Grant ERT-174211 (ProDGNE), and Network Grant OR2-189333 (NMD4C), from the Canada Foundation for Innovation (CFI-JELF 38412), the Canada Research Chairs Program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279), the European Commission (Grant # 101080249), and the Canada Research Coordinating Committee New Frontiers in Research Fund (NFRFG-2022-00033) for SIMPATHIC, and from the Government of Canada, Canada First Research Excellence Fund (CFREF) for the Brain-Heart Interconnectome (CFREF-2022-00007). KP holds a CIHR postdoctoral fellowship award under grant no. MFE-491707. This study makes use of data and tools shared/provided through the RD-Connect GPAP, which received funding originally from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement No. 305444.

Funder: Wolfson Foundation; doi:

Funder: Royal College of Physicians; doi:

Funder: Government of Canada Canada First Research Excellence Fund


CMT, Genetic heterogeneity, Genome-phenome analysis platform (GPAP), Mitochondrial disease, Peripheral neuropathies, Rare variants, Humans, Male, Female, Peripheral Nervous System Diseases, Adult, Mitochondrial Diseases, Middle Aged, Aged, Young Adult, Mutation, Mitochondrial Proteins, Cohort Studies, Adolescent, Charcot-Marie-Tooth Disease

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J Neurol

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Springer Science and Business Media LLC
Wellcome Trust (109915_A_15_Z)
MRC (MR/V009346/1)
National Institute for Health and Care Research (IS-BRC-1215-20014)