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

Yipu Zhang1, Jiayi Xu2, Wenxiu Chan1

  • 1Department of Cardiology, Shanghai Children's Medical Centre, Shanghai Jiao Tong University School of Medicine, No. 1678 Dongfang Road, Shanghai, 200127, China.

BMC Pediatrics
|July 21, 2026
PubMed

Insights

This study identifies compound heterozygous TOP3A pathogenic variants as a cause of severe, early-onset dilated cardiomyopathy (DCM) in children. The findings expand known genetic causes of pediatric DCM and highlight a critical need for genetic testing in affected children.

Area of Science:

  • Pediatric Cardiology
  • Genetics
  • Mitochondrial Disorders

Background:

  • Dilated cardiomyopathy (DCM) is the most common pediatric cardiomyopathy.
  • Etiology significantly impacts disease course and prognosis.
  • Mitochondrial disorders are an emerging cause of pediatric DCM.

Purpose of the Study:

  • To identify the genetic cause of early-onset DCM in three pediatric patients.
  • To characterize the cardiac phenotype associated with identified genetic variants.
  • To expand the known spectrum of DCM etiologies in children.

Main Methods:

  • Whole exome sequencing (WES) was performed on three pediatric patients with early-onset DCM.
  • Analysis focused on identifying pathogenic variants and assessing mitochondrial DNA copy number.

Main Results:

  • All three patients harbored compound heterozygous TOP3A pathogenic variants.
  • Reduced mitochondrial DNA copy number was observed in these patients.
  • The patients presented with rapid progression to end-stage heart failure, including two fatalities and one heart transplant.

Conclusions:

  • Compound heterozygous TOP3A pathogenic variants are a newly identified cause of severe pediatric dilated cardiomyopathy.
  • This finding broadens the genetic landscape of childhood DCM.
  • A severe cardiac phenotype is associated with TOP3A pathogenic variants.

Keywords:
TOP3A geneDilated cardiomyopathy (DCM)heart failuremtDNA deletionmtTopIIIα

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