Recurrent de novo ATAD3 duplications cause fatal perinatal mitochondrial cardiomyopathy, persistent hyperlactacidemia, encephalopathy and heart-specific mitochondrial oxidative phosphorylation complex i deficiency.

Mitochondrial disorders are clinically heterogeneous and comprise over 350 different genetic conditions. However, the molecular diagnosis is unknown in ~50% of cases, partly due to some genomic regions being refractory to standard genomic analysis. One such region is the ATAD3 locus consisting of 3 highly homologous tandemly arrayed genes (ATAD3C, ATAD3B and ATAD3A) encoding mitochondrial proteins implicated in processes including cholesterol metabolism, and mitochondrial replication, dynamics and morphology. Recessive deletions and dominant duplications in this locus have recently been reported to cause rare, lethal perinatal mitochondrial disorders characterised by pontocerebellar hypoplasia or cardiomyopathy, respectively. We report 17 subjects from 16 unrelated families with cardiomyopathy, persistent hyperlactacidemia, encephalopathy and frequently corneal clouding or cataracts due to de novo ATAD3 duplications. The six different 68 Kb duplications were consistently identifiable from whole genome and exome sequencing, but usually missed on microarray. The duplications all resulted in the formation of an identical chimeric ATAD3A/ATAD3C fusion protein, which appears to act in a dominant manner causing altered ATAD3 complexes and a striking reduction in mitochondrial oxidative phosphorylation complex I and its activity in heart tissue. In our experience, the ATAD3 locus is one of the five most common causes of nuclear-encoded paediatric mitochondrial disease but the repetitive nature of the locus means ATAD3 diagnoses may be frequently missed by current genomic strategies.