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May 14, 2025Scientific ReportsOpen Access

Combined nuclear and mitochondrial sequencing reveals synergistic variants disrupting myocardial bioenergetics in pediatric cardiomyopathy.

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Why the study?

Many cases of pediatric cardiomyopathy have no known etiology, prompting investigation into whether mitochondrial genome defects contribute to disease pathogenesis.

Does whole mitochondrial DNA sequencing combined with nuclear gene sequencing identify additional pathogenic variants in pediatric patients with primary non-syndromic cardiomyopathy?

Comparison

Pediatric cardiomyopathy patients vs healthy controls

Design

Case-control genetic sequencing study

Key result

Combined nuclear and mitochondrial DNA sequencing in 27 pediatric cardiomyopathy patients identified pathogenic nuclear variants in 7 patients and revealed additional mitochondrial variants that may synergistically disrupt myocardial bioenergetics.

Authors

MTMehmet Arda TemenaEGEbru Erzurumluoğlu GökalpESEzgi Susam

Discussion

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Overview

mtDNA sequencing may detect missed variants in unexplained pediatric cardiomyopathy; leaves open its diagnostic role pending validation.

Study Design

Type

Observational (n=58)

Multicenter

No

Structured PICO

Does whole mitochondrial DNA sequencing combined with nuclear gene sequencing identify additional pathogenic variants in pediatric patients with primary non-syndromic cardiomyopathy?

P
Population
58 children, comprising 27 with isolated non-syndromic primary cardiomyopathy and 31 healthy controls, underwent nuclear and mitochondrial DNA sequencing to investigate genetic etiologies.
E
Exposure
Two-stage sequencing approach: sequencing of a panel of 137 cardiomyopathy-related nuclear genes followed by whole mitochondrial DNA (mtDNA) sequencing.
C
Comparator
Healthy controls (for mtDNA sequencing comparison).
O
Outcome
Identification of pathogenic nuclear and mitochondrial DNA variants contributing to the etiology of pediatric cardiomyopathy.surrogate

Integrating whole mitochondrial DNA sequencing with nuclear gene panels reveals that mitochondrial variants may act synergistically with nuclear defects to drive pediatric cardiomyopathies.

Limitations

  • Small sample size due to the rarity of isolated non-syndromic pediatric primary cardiomyopathy.
  • Lack of in silico tools to evaluate human MT-RNR1 and MT-RNR2 variants.
  • Findings may not be generalizable to syndromic or secondary types of pediatric cardiomyopathy.
  • Did not evaluate the effect of TTN and PLEC variants in combination with other genes.
  • Limited sample size due to the rarity of isolated non-syndromic pediatric primary cardiomyopathy
  • Findings may not be generalizable to all forms of pediatric cardiomyopathy, particularly syndromic or secondary types
  • Lack of in silico tools to evaluate human MT-RNR1 and MT-RNR2 variants
  • Did not evaluate the effect of variants in combination with others in patients with TTN VUSs

Cite This Study

Temena et al. (2025) conducted an observational in Pediatric cardiomyopathies (n=58). Mitochondrial and nuclear genome variants vs. Healthy controls was evaluated on Identification of pathogenic nuclear and mitochondrial DNA variants. Combined nuclear and mitochondrial DNA sequencing in 27 pediatric cardiomyopathy patients identified pathogenic nuclear variants in 7 patients and revealed additional mitochondrial variants that may synergistically disrupt myocardial bioenergetics.

synapsesocial.com/papers/6a4c49effdb56635b009e3dehttps://doi.org/10.1038/s41598-025-01007-0
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Uncovering the Dual Role of Mitochondrial and Nuclear DNA Variants in Pediatric Cardiomyopathies2023
  2. 2High Prevalence of Genetic Alterations in Infantile-Onset Cardiomyopathy2021 · 1 citations
  3. 3Genetic Basis of Childhood Cardiomyopathy2022 · 65 citations
  4. 4Genomics of pediatric cardiomyopathy2025 · 13 citations
  5. 5OXPHOS defects and mitochondrial DNA mutations in cardiomyopathy1995 · 39 citations