Language
English
Publication Date
1-1-2025
Journal
Frontiers in Genetics
DOI
10.3389/fgene.2025.1488956
PMID
40110048
PMCID
PMC11920145
PubMedCentral® Posted Date
3-5-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Introduction: The 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.
Methods: Dual 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.
Results: The 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.
Conclusion: Variants 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.
Keywords
mitochondria, NGS, dual-genome, heteroplasmy, functional group analysis
Published Open-Access
yes
Recommended Citation
Gorman, Elizabeth; Dai, Hongzheng; Feng, Yanming; et al., "Experiences From Dual Genome Next-Generation Sequencing Panel Testing for Mitochondrial Disorders: A Comprehensive Molecular Diagnosis" (2025). Faculty and Staff Publications. 5008.
https://digitalcommons.library.tmc.edu/baylor_docs/5008
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