Identification of Nuclear Genetic Loci Linked to Clinical Features of the m.3243A>G Mitochondrial DNA Variant
Year: 2026
Type: article
Study design: Observational Study
Abstract: Background and Objectives: Mitochondrial DNA (mtDNA) disorders exhibit striking clinical variability that is poorly explained by known factors such as variant heteroplasmy, age, or sex. Nuclear genetic modifiers likely play a significant role in this heterogeneity. We aimed to characterize the nature of nuclear genetic involvement for 2 common syndromic presentations of the common pathogenic mtDNA variant, m.3243A>G: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and maternally inherited diabetes and deafness (MIDD). Methods: We assembled a multicenter cohort of clinically ascertained carriers of m.3243A>G (total n = 488), identifying 198 individuals across 76 pedigrees suitable for genetic linkage analysis. We investigated 4 clinical features characteristic of MELAS and MIDD: diabetes, hearing impairment, stroke-like episodes, and encephalopathy. Haseman-Elston regression-based genetic linkage analysis was performed to identify regions of the nuclear genome cosegregating with these features. The effects of m.3243A>G heteroplasmy, age, and sex were accounted for using logistic regression; empirical significance thresholds were determined through feature-specific gene-dropping simulations. Association analyses were performed in 247 individuals using single-variant (SAIGE) and gene-based approaches (SAIGE-GENE+ and MAGMA) to refine candidate loci within a significant linkage region. Results: ) as candidates, as each showed the strongest gene-level signals within the linkage region across complementary burden-testing methods, although neither reached corrected significance thresholds. Discussion: The nuclear genetic architecture modifying m.3243A>G differs across clinical features. Severe neurologic features (encephalopathy and stroke-like episodes) may be influenced by a small number of nuclear genes with relatively large effect sizes, whereas the nuclear contribution to diabetes and hearing impairment appears more polygenic. This study highlights the value of large, well-characterized patient cohorts in identifying modifier loci and advancing knowledge of the mechanisms underlying phenotypic variability in mtDNA disease.
Source: Neurology Genetics
Authors: Róisín M. Boggan, Theodora-Dafni Michalettou, Yi Shiau Ng, Imogen G. Franklin, Lucas T. Cortés, Charlotte L. Alston, Emma L. Blakely, Boriana Büchner, Enrico Bugiardini, Kevin Colclough, Catherine Feeney, Michael G. Hanna, Andrew T. Hattersley, Thomas Klopstock, Cornelia Kornblum, Michelangelo Mancuso, Kashyap A. Patel, Robert D.S. Pitceathly, Chiara Pizzamiglio, Holger Prokisch, Jochen Schäfer, Andrew M. Schaefer, Maggie H. Shepherd, Annemarie Thaele, Rhys H. Thomas, Doug M. Turnbull, Cathy E. Woodward, Robert McFarland, Robert W. Taylor, Heather J. Cordell, Sarah J. Pickett
Institutions: Newcastle University, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, LMU Klinikum, Ludwig-Maximilians-Universität München, National Health Service, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, University College London, Royal Devon & Exeter NHS Foundation Trust, Royal Devon University Healthcare NHS Foundation Trust, University of Exeter, German Center for Neurodegenerative Diseases, Munich Cluster for Systems Neurology, University Hospital Bonn, University of Pisa, Helmholtz Munich, Institut für Humangenetik, Technical University of Munich, University Hospital Carl Gustav Carus, Technische Universität Dresden, Martin Luther University Halle-Wittenberg
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,300
Funders: Wellcome Trust, Muscular Dystrophy UK, LifeArc, UK Research and Innovation, National Institute for Health and Care Research, University College London, Newcastle University, European Commission, Rosetrees Trust, Ministero della Salute, Ludwig-Maximilians-Universität München, Medical Research Council, NIHR Exeter Clinical Research Facility
OpenAlex ID: W7168491258