Hidden Diagnoses in Mitochondrial Disease: Under-detection of ATAD3A–ATAD3C Duplications in Clinical Genome Sequencing

June 20, 2026

Background

  • Recurrent ATAD3 locus duplications are an emerging cause of severe neonatal and pediatric mitochondrial disease.
  • ATAD3A–ATAD3C duplications are associated with a severe neonatal phenotype, including hypertrophic cardiomyopathy, persistent hyperlactatemia, corneal clouding/cataracts, encephalopathy, and early neonatal death.
  • The pathogenic mechanism is dominant-negative, as >91% of ATAD3 hexamers incorporate at least one dysfunctional fusion monomer despite monoallelic inheritance.
  • Detection is challenging due to high homology among ATAD3A, ATAD3B, and ATAD3C.
  • This complexity can lead to misinterpretation of copy number variants (CNVs) in routine genome sequencing (GS). As a result, aected individuals may remain undiagnosed despite clinical GS.
  • Study objective:
    • Evaluate the frequency of ATAD3A–ATAD3C duplications in a clinical cohort.
    • Identify factors contributing to under-recognition in diagnostic pipelines.