Mobile Menu

Genomic Sequencing to Explain New Rare Diseases

Determining the genetic basis of rare diseases is important for counselling and for developing our understanding of disease pathogenesis. While developments in genomic sequencing have allowed the identification of pathogenic single nucleotide variants, the larger and more complex mutations remain hard to detect. A recent study has tackled this problem, using genomic technologies to identify and characterise a specific causative mutation in patients with suspected mitochondrial disease.

Advances in Genomic Sequencing

Next generation sequencing technologies such as whole exome sequencing (WES) have facilitated the discovery of hundreds of genes associated with mitochondrial disease. However, a significant fraction of patients with suspicion of mitochondrial disease have remained without a genetic diagnosis. In many cases this is because while single nucleotide variants are easily detected by these screens, larger genomic rearrangements such as duplications, inversions or deletions can be more difficult to detect.

A recent study investigated patients suspected to have a mitochondrial disease, who presented with fatal perinatal cardiomyopathy and encephalopathy. Using a combination of genomic technologies and quantitative proteomics, the researchers identified a recurrent duplication as the molecular basis of this rare mitochondrial disease.


Mutations in the ATAD3 locus have previously been implicated in diseases with similar symptoms to the patients in this study. Thus, the researchers used whole genome sequencing (WGS) to characterise this locus in these patients. They identified a de novo duplication of the ATAD3 gene which disrupted the function of the ATAD3 proteins. These proteins play key roles in mitochondria function and the maintenance of mitochondrial DNA. The researchers also reported a striking deficiency in the function of the electron transport chain in patient heart tissue.

The ultimate identification of this genetic defect took years of work. Unfortunately, it currently seems unlikely that large and complex structural rearrangements could be confidently identified by WES data alone. For now, WGS and perhaps long read sequencing technologies are likely to be required for validating such results.

Clinical Applications

There are two practical outcomes of this study. Firstly, the clinical phenotype of this disease had remarkably similar core features in all patients investigated. Thus, future investigations in patients believed to have ATAD3 duplications can focus on the specific mutation identified in this study.

Finally, although there are currently no therapies for patients carrying ATAD3 duplications, the mutation always arose de novo. This significantly reduces the genetic risk of having another affected child, providing some consolation for the parents affected.

Picture Credit: Unsplash

More on these topics

Genetic Counselling / GWAS / Rare Diseases / WGS