Numerous studies have demonstrated the promise of whole-exome sequencing, which focuses on the protein-coding regions of DNA, but the clinical use of this technology has remained limited. Now, the largest report of results from this technology in a population of patients with undiagnosed disease of suspected hereditary origin highlights that the value of this testing is considerable, and that it can even uncover recessive mutations not previously linked to a given disease.

There are an increasing number of genetic tests for various illnesses, and doctors faced with a difficult-to-diagnose patient will order tests that look for mutations in a predetermined set of genes or larger chromosomal abnormalities, such as that detected by karyotype analysis. But the diagnostic success rate of such assays disappoints: karyotype analysis is only about 5% to 15%, and other methods generally fall below 20%.

A pilot study published today in the New England Journal of Medicine offers hope. It suggests that whole-exome sequencing might have as high as a 25% success rate in solving these hereditary disease mysteries. “For years we’ve known that whole-exome sequencing can identify new disease-causing mutations,” says Yaping Yang, a clinical geneticist at the Baylor College of Medicine in Houston and a study coauthor. “But this puts it on the map as a tool for clinical medicine.”

The researchers offered whole-exome sequencing, which cost about $7,000, as part of the medical care given to 250 people with undiagnosed diseases—many of whom were pediatric patients—who were referred by physicians after other methods, microarray analysis or tests looking at a single gene, failed to pinpoint the source of their illness. Whole-exome sequencing resulted in a genetic diagnosis for 62 of the patients, 20 of whom had autosomal recessive diseases—a less common finding because both parents must pass along a faulty copy of the given gene for clinical symptoms to arise. In some cases, patients had recessive mutations that hadn’t previously been reported as associated with their disease. For example, the researchers found one patient with two mutated copies of the spastic ataxia of Charlevoix-Saguenay gene, or ‘SACS’ gene, which included a new DNA deletion not previously known to cause this progressive movement disorder.

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