Abstract
In about half of all patients with a suspected monogenic disease, genomic investigations fail to identify the diagnosis. A contributing factor is the difficulty with repetitive regions of the genome, such as those generated by segmental duplications. The ATAD3 locus is one such region in which recessive deletions and dominant duplications have recently been reported to cause lethal perinatal mitochondrial diseases characterized by pontocerebellar hypoplasia or cardiomyopathy, respectively.
Whole-exome, whole-genome, and long-read DNA sequencing techniques combined with studies of RNA and quantitative proteomics were used to investigate 17 subjects from 16 unrelated families with suspected mitochondrial disease.
We report 6 different de novo duplications in the ATAD3 gene locus causing a distinctive presentation, including lethal perinatal cardiomyopathy, persistent hyperlactacidemia, and frequently, corneal clouding or cataracts and encephalopathy. The recurrent 68-kb ATAD3 duplications are identifiable from genome and exome sequencing but usually missed by microarrays. The ATAD3 duplications result in the formation of identical chimeric ATAD3A/ATAD3C proteins, altered ATAD3 complexes, and a striking reduction in mitochondrial oxidative phosphorylation complex I and its activity in heart tissue.
ATAD3 duplications appear to act in a dominant-negative manner and the de novo inheritance infers a low recurrence risk for families, unlike most pediatric mitochondrial diseases. More than 350 genes underlie mitochondrial diseases. In our experience, the ATAD3 locus is now one of the five most common causes of nuclear-encoded pediatric mitochondrial disease, but the repetitive nature of the locus means ATAD3 diagnoses may be frequently missed by current genomic strategies.
Australian NHMRC, US Department of Defense, US National Institutes of Health, Japanese AMED and JSPS agencies, Australian Genomics Health Alliance, and Australian Mito Foundation.
More than 350 genes causing mitochondrial diseases are known, but many patients remain undiagnosed. The authors identified 17 patients who died near birth due to a specific duplication of DNA in a repetitive region of the genome. The study shows that the duplication created a fusion between the ATAD3A and ATAD3C genes resulting in a stable protein that interfered with mitochondrial function. The duplication had been overlooked by conventional genomic investigations but can now be detected by re-analysis of existing genomic data from undiagnosed patients. The authors show that ATAD3 mutations are the most common cause of lethal infantile mitochondrial disease and that ATAD3 duplications are spontaneous events, meaning that families have a low risk of further affected children.
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De novo ATAD3 duplications lead to fatal perinatal mitochondrial cardiac failureStably expressed chimeric ATAD3A/ATAD3C protein disrupts ATAD3 oligomerizationDetection of copy number variants complicated by repetitive nature of ATAD3 locusATAD3 variants are among the most common causes of pediatric mitochondrial disease
Frazier et al. describe 17 patients with recurrent de novo ATAD3 duplications resulting in stably expressed chimeric ATAD3A/ATAD3C proteins and altered ATAD3 oligomerization. Affected individuals share striking clinical similarities featuring cardiomyopathy, perinatal death, and cardiac complex I deficiency, with ATAD3 emerging as a hotspot for pathogenic genomic variation leading to mitochondrial disease.