Genetic screening for mitchondrial diseases

28 October 2009

Mitochondrial disorders are a group of diseases, many very serious, caused by mutations in mitochondrial genes (see previous news). Together they have an estimated prevalence of around 1 in 5,000, and can affect multiple organs. Their clinical presentation is highly variable, and the underlying mutations may lie in one of hundreds of mitchondrial genes, most of which lie within the main genome in the cell nucleus, but a small number of which (thirteen) form the small separate mitochondrial genome.

Diagnosis of a mitchondrial disorders is therefore very difficult, but prompt and accurate diagnosis is important to allow effective treatment to minimise the potentially life-threatening disease progression. At the same time, some mutations associated with mitochondrial diseases also appear to be common in the general population; the penetrance of such mutations is also very variable, further complicating the clinical picture.

Now US researchers have used a combination of next-generation sequencing (see previous news) and microarray technology to create a new screening technique to identify mitchondrial mutations. Publishing in the open access journal Genome Medicine, they report the use of this technique to screen for variations in all the mitochondrial genes and a total of 362 nuclear genes previously associated with mitochondrial function or disease [Vasta V et al. (2009) Genome Med. 1(10):100].

The screen was tested on three DNA samples, two from previously characterised patients with known mitochondrial disorders and one control sample from the HapMap resource (see previous news). Both known mutations were correctly identified by the screen. In addition, the researchers reported detection of up to 336 further variants for each DNA sample, of which 90-94% were recorded in existing SNP databases and 6-10% were novel. One of these new variants was thought to be potentially harmful.

The authors propose that their molecular diagnostic tool “will increase the capacity for early and rapid identification of mitochondrial disorders” and potentially also help in the ongoing investigation of mutations associated with the conditions. They note that as more information is recorded about genetic variants associated with mitchondrial disease, there will be decreasing requirements for investigation of potentially harmful new mutations identified by screening.

Comment: The authors themselves acknowledge that the new screening technique requires considerable further development – three patient samples being on the small side even for a proof-of-concept study – but are right to assert that further analysis of mitochondrial mutations (which could be facilitated by methods such as their own) is likely to help expand understanding of this group of serious genetic disorders.

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