TOP3A pathogenic variants presenting as dilated cardiomyopathy and heart failure in three pediatric cases

Q: What is the clinical evidence from this study?

Study design: Case Report. Population: Dilated cardiomyopathy and heart failure (n=3). Intervention: TOP3A pathogenic variants. Primary outcome: Clinical progression and mortality.

Q: What does this research mean for the field?

Compound heterozygous pathogenic variants in TOP3A cause early-onset dilated cardiomyopathy with reduced mitochondrial DNA copy number and rapid progression to end-stage heart failure in pediatric patients. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Yipu Zhang; Jiayi Xu; Wenxiu Chan; H Z Chen; Jinjin Wu; Ying Guo; Ruen Yao; L Fu

doi:10.1186/s12887-026-07361-w

July 21, 2026BMC PediatricsOpen Access

TOP3A pathogenic variants presenting as dilated cardiomyopathy and heart failure in three pediatric cases

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Key result

Biallelic TOP3A variants are linked to rapid progression to end-stage heart failure in pediatric DCM.

n=3

Why the study?

Dilated cardiomyopathy etiology critically influences prognosis, and mitochondrial disorders represent a rare but increasingly recognized cause of pediatric DCM.

Key Points

To describe the clinical, genetic, and mitochondrial characteristics of early-onset dilated cardiomyopathy and heart failure caused by pathogenic TOP3A variants in pediatric patients.
Evaluated three pediatric patients presenting with early-onset dilated cardiomyopathy (DCM) at ages 8, 9, and 8 years at a clinical center (retrospectively registered at Chinese Clinical Trial Registry: ChiCTR2600117173).
Conducted whole exome sequencing (WES) to detect causative variants following poor response to standard DCM treatments.
Quantified peripheral blood mitochondrial DNA (mtDNA) copy numbers using quantitative PCR assays in all three patients compared to control levels.
Identified compound heterozygous TOP3A pathogenic variants across all three patients, corresponding with significantly reduced peripheral blood mitochondrial DNA copy numbers compared with control levels.
Documented rapid progression to end-stage heart failure and multiorgan failure refractory to standard DCM therapy, resulting in fatalities in two patients at 10 and 14 months post-onset and cardiac transplantation in one patient after 2 months.
Observed electrophysiological conduction abnormalities in all cases, including premature ventricular contractions that advanced to complete right bundle branch block and atrioventricular block, alongside pediatric-onset chronic progressive external ophthalmoplegia in one patient.

Study Design

Type

Case Report (n=3)

Multicenter

No

Structured PICO

P

Population

Three pediatric patients (ages 8-10, 67% female) with early-onset dilated cardiomyopathy who rapidly progressed to end-stage heart failure.

O

Outcome

Identification of genetic etiology via whole exome sequencing and clinical progression of the disease.

TOP3A pathogenic variants can present as early-onset pediatric dilated cardiomyopathy with rapid progression to end-stage heart failure, expanding the recognized etiologies of childhood DCM.

Limitations

Fresh skeletal muscle biopsy or endomyocardial biopsy was not performed.
Functional assessments of residual mitochondrial gene activity were not conducted.
Direct functional assays, such as enzyme activity tests or animal models, were lacking.
Inability to obtain fresh peripheral blood samples for sister chromatid exchange comparison due to patient mortality.
Lack of fresh skeletal muscle biopsy or endomyocardial biopsy.
Inability to perform microscopic examination of sister chromatid exchange events due to patient deaths.

Implication

May support TOP3A screening in severe early-onset pediatric dilated cardiomyopathy; hypothesis-generating and requires validation in larger cohorts.

Abstract

Dilated cardiomyopathy (DCM) is the most prevalent form of cardiomyopathy in children, characterized by left ventricle dilation and impaired systolic function. The etiology critically influences clinical trajectory and prognosis. Mitochondrial disorders represent a rare but increasingly recognized cause of DCM. Herein, we report three pediatric patients, diagnosed with early-onset DCM at ages of 8, 9, and 8, who progressed rapidly to end stage heart failure, resulting in two fatalities and one cardiac transplantation. Whole exome sequencing (WES) analysis identified compound heterozygous TOP3A pathogenic variants in all three cases, accompanied by reduced mitochondrial DNA copy number. Therefore, this report expands the recognized etiologies of childhood DCM and delineates a severe cardiac phenotype within the TOP3A pathogenic variant spectrum. Trial Registration: Registered at Chinese Clinical Trial Registry (ChiCTR2600117173). Registered 20/01/2026. Retrospectively registered.

Discussion

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Cite This Study

Zhang et al. (2026) conducted a case report in Dilated cardiomyopathy and heart failure (n=3). TOP3A pathogenic variants was evaluated on Clinical progression and mortality. Compound heterozygous TOP3A pathogenic variants were identified in three pediatric patients with early-onset dilated cardiomyopathy who rapidly progressed to end-stage heart failure, resulting in two fatalities and one cardiac transplantation.

synapsesocial.com/papers/6a61afaefaa9903c5116a716 https://doi.org/10.1186/s12887-026-07361-w

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TOP3A pathogenic variants presenting as dilated cardiomyopathy and heart failure in three pediatric cases

Key Points

Study Design

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

TOP3A pathogenic variants presenting as dilated cardiomyopathy and heart failure in three pediatric cases

Key Points

Study Design

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

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