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However, the mutation spectrum of mitochondrial DNA (mtDNA) in the Chinese population remains incomplete. Therefore, the primary objective of our study was to comprehensively characterize pathogenic mtDNA variants in Chinese children with mitochondrial disorders at clinical, molecular, and functional levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Between February 2019 and September 2023, we analyzed pathogenic mtDNA variants in a cohort of over 600 Chinese children suspected of having mitochondrial disorders. Whole\u2010exome sequencing (WES) and whole\u2010mtDNA sequencing were performed on the cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 54 pathogenic or likely pathogenic mtDNA variants in 227 Chinese children with neurological mitochondrial disorders. Among the eight novel heteroplasmic variants detected in seven patients,\n                      <jats:italic>in silico<\/jats:italic>\n                      analyses suggested likely pathogenic features. Functional analyses using either primary fibroblasts or cybrid cells carrying different mutant loads of mtDNA variants showed impaired mitochondrial respiration, ATP generation, and mitochondrial membrane potential in five of the eight novel variants, including m.4275G&gt;A, m.10407G&gt;A, m.5828G&gt;A, m.3457G&gt;A, and m.13112T&gt;C. The m.8427T&gt;C variant was identified as a rare polymorphism because, despite being located at MT\u2010ATP8, it does not affect both the assembly and activity of mitochondrial complex V in cells carrying homoplasmic m.8427T&gt;C variation. Transcriptome profiling further confirmed the pathogenic contributions of these five variants by altering mitochondrial pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In summary, we revisited the mtDNA mutation spectrum in Chinese children with mitochondrial disorders, and identified five novel pathogenic mtDNA variants with functional verification that are related to neurological mitochondrial disorders in children.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.52315","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T13:54:21Z","timestamp":1738850061000},"page":"586-601","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Novel pathogenic\n                    <scp>mtDNA<\/scp>\n                    variants in Chinese children with neurological mitochondrial disorders"],"prefix":"10.1002","volume":"12","author":[{"given":"Zhimei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neurology, Beijing Children\u2019s Hospital Capital Medical University, National Center for Children\u2019s Health  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1172-6774","authenticated-orcid":false,"given":"Kexin","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Blood Transfusion The First Affiliated Hospital of Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzhao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children\u2019s Hospital Capital Medical University, National Center for Children\u2019s Health  Beijing 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