Abstract
Abstract
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.
Funder
Medical Research Council
Wellcome Trust
Addenbrooke's Charitable Trust, Cambridge University Hospitals
Lily Foundation
Action for A-T
Muscular Dystrophy UK
NIHR Cambridge Biomedical Research Centre
Wolfson Foundation
Royal College of Physicians
CIHR
Transnational Team Grant
Canada Foundation for Innovation
Canada Research Chairs
Canada Research Coordinating Committee
Government of Canada Canada First Research Excellence Fund
Canadian Institute for Health Research
Evelyn Trust
Publisher
Springer Science and Business Media LLC
Reference40 articles.
1. Hicks CW, Selvin E (2019) Epidemiology of peripheral neuropathy and lower extremity disease in diabetes. Curr DiabRep 19:1–8
2. Martyn C, Hughes R (1997) Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry 62(4):310
3. Eggermann K, Gess B, Häusler M, Weis J, Hahn A, Kurth I (2018) Hereditary neuropathies: clinical presentation and genetic panel diagnosis. Dtsch Arztebl Int 115(6):91
4. Morena J, Gupta A, Hoyle JC (2019) Charcot-Marie-Tooth: from molecules to therapy. Int J Mol Sci 20(14):3419
5. Horvath R, Medina J, Reilly MM, Shy ME, Zuchner S (2023) Peripheral neuropathy in mitochondrial disease. Handbook of clinical neurology. 194: Elsevier, p. 99–116.
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献