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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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>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\u2019 genetic data were then analysed and searched for variants in known mitochondrial disease genes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>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 <jats:italic>GDAP1<\/jats:italic> and <jats:italic>GARS1<\/jats:italic>. We also detected heterozygous likely pathogenic variants in <jats:italic>DNA2, MFN2<\/jats:italic>, <jats:italic>DNM2, PDHA1, SDHA,<\/jats:italic> and <jats:italic>UCHL1<\/jats:italic>. Biallelic variants in <jats:italic>SACS, SPG7<\/jats:italic>, <jats:italic>GDAP1, C12orf65, UCHL1, NDUFS6, ETFDH<\/jats:italic> and <jats:italic>DARS2<\/jats:italic> and variants in the mitochondrial DNA (mtDNA)-encoded <jats:italic>MT-ATP6<\/jats:italic> and <jats:italic>MT-TK<\/jats:italic> were also causative for mitochondrial CMT. Only 50% of these variants were already reported as solved in GPAP.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>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.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00415-024-12319-y","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T17:01:50Z","timestamp":1711645310000},"page":"3546-3553","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies"],"prefix":"10.1007","volume":"271","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1465-522X","authenticated-orcid":false,"given":"Tomas","family":"Ferreira","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8879-6001","authenticated-orcid":false,"given":"Kiran","family":"Polavarapu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0112-5767","authenticated-orcid":false,"given":"Catarina","family":"Olimpio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8666-6054","authenticated-orcid":false,"given":"Ida","family":"Paramonov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2324-8001","authenticated-orcid":false,"given":"Hanns","family":"Lochm\u00fcller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9841-170X","authenticated-orcid":false,"given":"Rita","family":"Horvath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,3,28]]},"reference":[{"key":"12319_CR1","first-page":"1","volume":"19","author":"CW Hicks","year":"2019","unstructured":"Hicks CW, Selvin E (2019) Epidemiology of peripheral neuropathy and lower extremity disease in diabetes. 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