Tag Archives: DNA

Whole-exome sequencing rises to top in largest clinical application for undiagnosed disease

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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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Anonymity not guaranteed: Identity of personal genomic DNA revealed by Web search

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A few decades ago, people might have looked at you funny if you asked them to publicly share the intimate details of their personal lives—where they live, their age, what they had for dinner a few nights ago, photos of their children and more. However, between Facebook, Google, LinkedIn and the rest, it’s almost a trivial matter to find out people’s private details today. And soon, a new study suggests, your entire genome could get added to that list of personal information so easily found online—whether you want it or not.

“The issue is the current status of privacy,” says Yaniv Erlich, a geneticist at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, who led the research. “We need [sponsors of genomic studies] to be respectful to participants, to tell them the truth: that someone can identify you.”

To lift the mask off of genomic data that had been seemingly stripped of identifying information, Erlich and his team focused on the Y-chromosome, typically passed along with surnames from fathers to sons. Genetic ancestry services such as FamilyTreeDNA and Ancestry.com allow customers to trace their paternal genealogy through an analysis of a series of genetic markers known as short tandem repeats on the Y-chromosome (Y-STRs). As a free service, many of these companies also share their large databases of Y-STRs, with accompanying surnames and built-in search engines, to the public. Since demographic information, including year of birth and state of residency, are often included in published scientific reports, and can also be linked to surname records on sites such as such as PeopleFinders.com or USApeople-search.com, it proved relatively straightforward for Erlich and his colleagues to narrow the identity of DNA contributors down to small lists of likely suspects.

As an example, they tested their procedure on 10 ‘anonymous’ personal genomes, taken from the 1000Genomes project and the European Nucleotide Archive. They recovered surnames for half of these men with a high probability of accuracy. After an internet search, they identified not only the individuals to whom the genomes belonged, but their entire family trees. The findings were published today in Science.

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Microfluidic chips offer a SMART-er way to detect flu

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Tracking influenza outbreaks quickly and cheaply could get a whole lot easier thanks to a number of experimental devices that can accurately detect viral strains in an hour or so. Using microfluidic techniques, these ‘flu chips’ could lead to better disease surveillance and treatment

“We want to see better tests in the outpatient setting so physicians can get the best information available,” says CDC epidemiologist Dan Jernigan. “Within the last year we a have seen a number of these tests being developed.”

In March, Catherine Klapperich and her colleagues at Boston University described a miniaturized device embedded with tiny tubes that could extract flu RNA from a sample and amplify it using reverse-transcriptase polymerase chain reactions (RT-PCR) with 96% sensitivity. To her knowledge, no other assay previously used one chip for both tasks using a cohort of human samples.

In another first, Anubhav Tripathi and his colleagues at Brown University in Providence, Rhode Island, have developed a technique that relies on a DNA probe that binds and amplifies target viral RNA without relying on RT-PCR — a system the authors call a ‘Simple Method for Amplifying RNA Targets,’ or SMART. Reporting today in the Journal of Molecular Diagnostics, the researchers found that the SMART assay accurately detected flu in the lab, with studies involving clinical specimens underway to confirm the results. “They have done that through creative engineering of the primer and probes, and reengineering the assay development from the beginning,” says Klapperich, who was not involved in the Brown University study.

Importantly, unlike most laboratory-based assays currently approved for influenza testing by the US Centers for Disease Control and Prevention (CDC), these new point-of-care devices can be run under field conditions, thereby reducing the time from isolate sampling to diagnosis that can delay the pace of pandemic monitoring.

Beyond influenza, many groups are working on similar point-of-care diagnostics for a slew of other infectious diseases, too. Click below for a video about a new rapid and affordable way to detect HIV and syphilis in a developing world setting (as reported last year in Nature Medicine).

Image courtesy of anyaivanova via Shutterstock