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Identification of nuclear genetic loci linked to clinical features of the m.3243A>G mitochondrial DNA variant.
Neurol. Genet. 12:e200411 (2026)
Background and ObjectivesMitochondrial
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).MethodsWe
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.ResultsWe
identified significant genetic linkage to encephalopathy (chromosome
7q22; LOD = 3.72), and regions suggestive of genetic linkage on
chromosomes 1, 5, 6, 11, and 13, for encephalopathy and stroke-like
episodes. No linkage was identified for diabetes or hearing impairment.
Association analysis within the chromosome 7 region identified variant
rs62500792 (intergenic between SDHAF3 and TAC1) with the lowest p value (3.7 × 10−5), yet no variants reached the proportional significance threshold (5.3 × 10−6). Gene-based analyses highlighted PLOD3 (p = 3.9 × 10−3) and IMMP2L (p = 6.4 × 10−3)
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.DiscussionThe
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Mitochondrial Dna ; Nuclear Dna ; Mitochondrial Disease ; Identification (biology) ; Nuclear Gene ; Mitochondrion ; Dna ; Genetic Analysis
ISSN (print) / ISBN
2376-7839
e-ISSN
2376-7839
Journal
Neurology Genetics
Quellenangaben
Volume: 12,
Issue: 4,
Article Number: e200411
Publisher
American Academy of Neurology
Publishing Place
Minneapolis, Minn.
Reviewing status
Peer reviewed
Institute(s)
Institute of Neurogenomics (ING)