{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:56:41Z","timestamp":1790873801637,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Introduction: Parkinson\u2019s disease (PD) is a prevalent neurodegenerative disorder, with several proposed pathogenic mechanisms. Given the established role of mitochondrial dysfunction in PD, this study seeks to investigate the enrichment of rare genetic variants tied to mitochondrial metabolism in cases of early-onset and familial PD. Methods: We performed a retrospective analysis on 248 early-onset and familial PD patients and 1622 control individuals. We assessed both pathway-level and gene-level burden of germline rare variants detected using exome sequencing in 467 nuclear genes related to mitochondrial metabolism. Results: Gene-set mutation burden analysis indicated an increased burden in genes associated with mtDNA maintenance. In addition, gene-level analysis identified a possible association between PD and rare variant burden in 14 mitochondrial metabolism-related genes under dominant or recessive inheritance models. Conclusions: Our findings support a potential contribution of rare germline variants affecting mitochondrial metabolism to the susceptibility in early-onset and familial PD.<\/jats:p>","DOI":"10.3390\/genes17040472","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T11:53:46Z","timestamp":1776426826000},"page":"472","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Enrichment of Rare Variants in Nuclear-Encoded Mitochondrial Metabolism Genes in Patients with Early-Onset or Familial Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4498-1042","authenticated-orcid":false,"given":"Gaber","family":"Bergant","sequence":"first","affiliation":[{"name":"Clinical Institute for Genomic Medicine, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4653-8503","authenticated-orcid":false,"given":"Vesna M.","family":"van Midden","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3998-3609","authenticated-orcid":false,"given":"Polina","family":"Tsygankova","sequence":"additional","affiliation":[{"name":"Clinical Institute for Genomic Medicine, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorian","family":"Laslo","sequence":"additional","affiliation":[{"name":"Clinical Institute for Genomic Medicine, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentino","family":"Ra\u010dki","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1832-3441","authenticated-orcid":false,"given":"Dejan","family":"Georgiev","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia"},{"name":"Artificial Intelligence Lab, Faculty of Computer and Information Sciences, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4405-5460","authenticated-orcid":false,"given":"Eli\u0161a","family":"Papi\u0107","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5208-147X","authenticated-orcid":false,"given":"Marija","family":"Brankovi\u0107","sequence":"additional","affiliation":[{"name":"Department for Clinical Genetics, University Children\u2019s Hospital, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3939-9739","authenticated-orcid":false,"given":"Milena","family":"Jankovi\u0107","sequence":"additional","affiliation":[{"name":"Neurology Clinic, University Clinical Center of Serbia, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Svetel","sequence":"additional","affiliation":[{"name":"Neurology Clinic, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nata\u0161a","family":"Teran","sequence":"additional","affiliation":[{"name":"Clinical Institute for Genomic Medicine, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasa Dragasevi\u0107","family":"Miskovi\u0107","sequence":"additional","affiliation":[{"name":"Neurology Clinic, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2669-8251","authenticated-orcid":false,"given":"Igor","family":"Petrovi\u0107","sequence":"additional","affiliation":[{"name":"Neurology Clinic, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ale\u0161","family":"Maver","sequence":"additional","affiliation":[{"name":"Clinical Institute for Genomic Medicine, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Novakovi\u0107","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Neurology Clinic, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5495-944X","authenticated-orcid":false,"given":"Zvezdan","family":"Pirto\u0161ek","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia"},{"name":"Department of Neurology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4433-3985","authenticated-orcid":false,"given":"Martin","family":"Raku\u0161a","sequence":"additional","affiliation":[{"name":"Division of Neurology, University Medical Centre Maribor, 2000 Maribor, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimira","family":"Vuleti\u0107","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7824-4978","authenticated-orcid":false,"given":"Borut","family":"Peterlin","sequence":"additional","affiliation":[{"name":"Clinical Institute for Genomic Medicine, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s00702-017-1686-y","article-title":"Epidemiology of Parkinson\u2019s disease","volume":"124","author":"Tysnes","year":"2017","journal-title":"J. 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