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UK Research Team Explores Exome Sequencing for Muscular Dystrophy Diagnosis

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By Julia Karow

A team of researchers led by the University of Nottingham in the UK has shown that exome sequencing can provide an accurate molecular diagnosis for muscular dystrophy, making it suitable in principle for diagnostic use.

In a proof-of-concept study published online in the European Journal of Human Genetics last month, the scientists used exome sequencing to analyze a sample from a biobank whose donor had been diagnosed with a certain type of muscular dystrophy and found a mutation that pointed to a different type of the disease. "Diagnosis by sequencing," they concluded, is likely to become commonplace in genetic diagnostic laboratories in the future.

Next-gen sequencing is already being used to diagnose heterogeneous inherited disorders that can be caused by a number of different genes, such as cardiomyopathies or hearing loss.

Muscular dystrophy is another disease that fits this bill, according to Jane Hewitt, a professor of mammalian genetics at the Centre for Genetics and Genomics at the University of Nottingham and the senior author of the study. "Genetically, it's very heterogeneous, and the phenotypes are quite overlapping, so you can't always look at someone and know exactly which gene might be mutated," she said. Overall, more than 50 genetic loci are known to play a role in the disease.

For their study, the scientists analyzed several samples from the Coriell Cell Repository whose donors had been clinically diagnosed with a type of the disease called facioscapulohumeral muscular dystrophy, or FSHD. But when they ran a number of molecular tests on one of those samples to confirm the diagnosis for their project, they found that the results were incompatible with FSHD, so they decided to look for a molecular cause by exome sequencing.

For their exome analysis, they used Agilent's SureSelect platform coupled with Illumina paired-end sequencing. After filtering the 33,500 single-nucleotide variants they found against dbSNP and the 1000 Genomes Project database, they were left with 435 nonsense or missense mutations, as well as 51 indels. Filtering those further against 48 genes that are associated with muscular dystrophies, they found two different variants in the CAPN3 gene that had previously been shown to cause limb-girdle muscular dystrophy type 2A.

The exome analysis, conducted in a research lab, cost several thousand euros, according to Hewitt, which was no more expensive than sequencing each candidate gene individually. Exome sequencing was also quicker than a gene-by-gene approach would have been.

Once the cost of exome sequencing comes down further, she said, the approach — sequencing the entire exome but restricting the analysis to known pathogenic genes — might become a cost-effective way of diagnosing muscular dystrophy molecularly, which she said is currently done on a gene-by-gene basis, guided by educated guesses of clinicians.

Exome sequencing might be a better approach than sequencing gene panels, she said, because if no mutation is found initially but new disease genes are discovered later, "you can go back and look at the data; it's still there."

The greatest challenge for introducing an exome-sequencing test more routinely will be data interpretation. "It's really the link between the DNA sequence and the clinician," she said, and the solution will likely be a combination of new software and bioinformatics expertise.

Kate Bushby, one of the leaders of the Newcastle Muscle Centre at the Institute of Genetic Medicine of Newcastle University, agreed. "As a heterogeneous group of disorders, where diagnosis can be challenging, the concept of rapid sequencing of a number of genes for [neuromuscular dystrophy] simultaneously holds great promise," she said.

However, as in other disease areas, "quality control, the non-availability of excellent bioinformatics solutions, and a clear process by which to develop key clinical correlates remain the major barriers to implementation of these kinds of solutions in the diagnostic setting."

According to Bushby, current technologies can already diagnose the majority of patients with NMD, though they may take some time. "Moving to a new system will require careful testing and multidisciplinary assessment of the range of potential mutations detected," she said.


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