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

UMDF Poster (2026)

All Publications

PMID

Publication AuthorsChong ML, Rosenfeld JA, Zhu W, Sinson J, Driver M, Rigobello R, Kao E, Wu W, Wang Y, Scaglia F, Liu P, Undiagnosed Diseases Network, Andersson H, Burrage L, Dai H

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.
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