Experiences from dual genome next-generation sequencing panel testing for mitochondrial disorders: a comprehensive molecular diagnosis
IntroductionThe molecular diagnosis of mitochondrial disorders is complicated by phenotypic variability, genetic heterogeneity, and the complexity of mitochondrial heteroplasmy. Next-generation sequencing (NGS) of the mitochondrial genome in combination with a targeted panel of nuclear genes associa...
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Frontiers Media S.A.
2025-03-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2025.1488956/full |
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| author | Elizabeth Gorman Hongzheng Dai Hongzheng Dai Yanming Feng William James Craigen William James Craigen David C. Y. Chen Fan Xia Fan Xia Linyan Meng Linyan Meng Pengfei Liu Pengfei Liu Robert Rigobello Arpita Neogi Christine M. Eng Christine M. Eng Yue Wang Yue Wang |
| author_facet | Elizabeth Gorman Hongzheng Dai Hongzheng Dai Yanming Feng William James Craigen William James Craigen David C. Y. Chen Fan Xia Fan Xia Linyan Meng Linyan Meng Pengfei Liu Pengfei Liu Robert Rigobello Arpita Neogi Christine M. Eng Christine M. Eng Yue Wang Yue Wang |
| author_sort | Elizabeth Gorman |
| collection | DOAJ |
| description | IntroductionThe molecular diagnosis of mitochondrial disorders is complicated by phenotypic variability, genetic heterogeneity, and the complexity of mitochondrial heteroplasmy. Next-generation sequencing (NGS) of the mitochondrial genome in combination with a targeted panel of nuclear genes associated with mitochondrial disease provides the highest likelihood of obtaining a comprehensive molecular diagnosis. To assess the clinical utility of this approach, we describe the results from a retrospective review of patients having dual genome panel testing for mitochondrial disease.MethodsDual genome panel testing by NGS was performed on a cohort of 1,509 unrelated affected individuals with suspected mitochondrial disorders. This test included 163 nuclear genes associated with mitochondrial diseases and the entire mitochondrial genome. A retrospective review was performed to evaluate diagnostic yield, disease-gene contributions, and heteroplasmy levels of pathogenic/likely pathogenic (P/LP) mitochondrial DNA (mtDNA) variants.ResultsThe overall diagnostic yield was 14.6%, with 7.7% from the nuclear genome and 6.9% from the mtDNA genome. P/LP variants in nuclear genes were enriched in both well-established genes (e.g., POLG) and more recently described genes (e.g., FBXL4), highlighting the importance of keeping the panel design updated.ConclusionVariants in nuclear and mitochondrial genomes equally contributed to a 14.6% diagnostic yield in this patient cohort. Dual genome NGS testing provides a comprehensive framework for diagnosing mitochondrial disorders, offering clinical utility that can be considered as first-tier approach compared to single genome testing. Characterizing disease-causing genes, variants, and mtDNA heteroplasmy enhances understanding of mitochondrial disorders. Testing alternative tissues can further increase diagnostic yield. |
| format | Article |
| id | doaj-art-cd3e4dfee2c842c0b533c786a15c990f |
| institution | OA Journals |
| issn | 1664-8021 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Genetics |
| spelling | doaj-art-cd3e4dfee2c842c0b533c786a15c990f2025-08-20T02:02:01ZengFrontiers Media S.A.Frontiers in Genetics1664-80212025-03-011610.3389/fgene.2025.14889561488956Experiences from dual genome next-generation sequencing panel testing for mitochondrial disorders: a comprehensive molecular diagnosisElizabeth Gorman0Hongzheng Dai1Hongzheng Dai2Yanming Feng3William James Craigen4William James Craigen5David C. Y. Chen6Fan Xia7Fan Xia8Linyan Meng9Linyan Meng10Pengfei Liu11Pengfei Liu12Robert Rigobello13Arpita Neogi14Christine M. Eng15Christine M. Eng16Yue Wang17Yue Wang18Baylor Genetics, Houston, TX, United StatesBaylor Genetics, Houston, TX, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesBaylor Genetics, Houston, TX, United StatesBaylor Genetics, Houston, TX, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesBaylor Genetics, Houston, TX, United StatesBaylor Genetics, Houston, TX, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesBaylor Genetics, Houston, TX, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesBaylor Genetics, Houston, TX, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesBaylor Genetics, Houston, TX, United StatesBaylor Genetics, Houston, TX, United StatesBaylor Genetics, Houston, TX, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesBaylor Genetics, Houston, TX, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesIntroductionThe molecular diagnosis of mitochondrial disorders is complicated by phenotypic variability, genetic heterogeneity, and the complexity of mitochondrial heteroplasmy. Next-generation sequencing (NGS) of the mitochondrial genome in combination with a targeted panel of nuclear genes associated with mitochondrial disease provides the highest likelihood of obtaining a comprehensive molecular diagnosis. To assess the clinical utility of this approach, we describe the results from a retrospective review of patients having dual genome panel testing for mitochondrial disease.MethodsDual genome panel testing by NGS was performed on a cohort of 1,509 unrelated affected individuals with suspected mitochondrial disorders. This test included 163 nuclear genes associated with mitochondrial diseases and the entire mitochondrial genome. A retrospective review was performed to evaluate diagnostic yield, disease-gene contributions, and heteroplasmy levels of pathogenic/likely pathogenic (P/LP) mitochondrial DNA (mtDNA) variants.ResultsThe overall diagnostic yield was 14.6%, with 7.7% from the nuclear genome and 6.9% from the mtDNA genome. P/LP variants in nuclear genes were enriched in both well-established genes (e.g., POLG) and more recently described genes (e.g., FBXL4), highlighting the importance of keeping the panel design updated.ConclusionVariants in nuclear and mitochondrial genomes equally contributed to a 14.6% diagnostic yield in this patient cohort. Dual genome NGS testing provides a comprehensive framework for diagnosing mitochondrial disorders, offering clinical utility that can be considered as first-tier approach compared to single genome testing. Characterizing disease-causing genes, variants, and mtDNA heteroplasmy enhances understanding of mitochondrial disorders. Testing alternative tissues can further increase diagnostic yield.https://www.frontiersin.org/articles/10.3389/fgene.2025.1488956/fullmitochondriaNGSdual-genomeheteroplasmyfunctional group analysis |
| spellingShingle | Elizabeth Gorman Hongzheng Dai Hongzheng Dai Yanming Feng William James Craigen William James Craigen David C. Y. Chen Fan Xia Fan Xia Linyan Meng Linyan Meng Pengfei Liu Pengfei Liu Robert Rigobello Arpita Neogi Christine M. Eng Christine M. Eng Yue Wang Yue Wang Experiences from dual genome next-generation sequencing panel testing for mitochondrial disorders: a comprehensive molecular diagnosis Frontiers in Genetics mitochondria NGS dual-genome heteroplasmy functional group analysis |
| title | Experiences from dual genome next-generation sequencing panel testing for mitochondrial disorders: a comprehensive molecular diagnosis |
| title_full | Experiences from dual genome next-generation sequencing panel testing for mitochondrial disorders: a comprehensive molecular diagnosis |
| title_fullStr | Experiences from dual genome next-generation sequencing panel testing for mitochondrial disorders: a comprehensive molecular diagnosis |
| title_full_unstemmed | Experiences from dual genome next-generation sequencing panel testing for mitochondrial disorders: a comprehensive molecular diagnosis |
| title_short | Experiences from dual genome next-generation sequencing panel testing for mitochondrial disorders: a comprehensive molecular diagnosis |
| title_sort | experiences from dual genome next generation sequencing panel testing for mitochondrial disorders a comprehensive molecular diagnosis |
| topic | mitochondria NGS dual-genome heteroplasmy functional group analysis |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2025.1488956/full |
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