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Biomedicine

A Test for 400 Inherited Diseases

New technology will allow broad screening for prospective parents.

Researchers have developed a new test designed to simultaneously detect genetic mutations involved in more than 400 severe diseases. The test, which was shown to be highly accurate, is initially aimed at screening prospective parents for mutations linked to rare inherited disorders.

Spotting disease: The white column in the middle of this DNA sequence chart highlights a four-letter deletion in the genome that is linked to a disorder called Lesch-Nyan syndrome. The disorder, which strikes in infancy, causes severe mental and physical problems.

Thanks to inexpensive sequencing technology, scientists aim to offer the test for just a few hundred dollars, similar to the cost of tests currently available for detecting individual diseases or a handful of disorders.

“We want this test to become available in the same way Tay-Sachs and cystic-fibrosis testing has,” says Stephen Kingsmore, chief scientific officer of the National Center for Genome Resources and senior author on the study. Tay-Sachs, a rare inherited disorder, strikes in infancy and is typically fatal within the first few years of life. “Forty years of experience with Tay-Sachs resulted in that awful disorder becoming pretty much eradicated in North America,” he says. “This is just on a grander scale.”

The new test, which reads the sequence of about 2 million letters of DNA spread out over 7,000 different chunks, is designed to detect mutations in genes that have been linked to so-called recessive Mendelian disorders, including cystic fibrosis and Tay-Sachs. People who inherit two mutant copies of the relevant gene are guaranteed to develop the disease, while people with only one copy will not. These diseases often strike early in life with severe consequences, including severe disability and death. And while they are individually rare, together they account for about 20 percent of infant mortality.

Testing prospective parents for these mutations can help them prevent or plan for the diseases. Couples who are both carriers of mutations in a particular disease-linked gene could choose to adopt, to conduct genetic tests on in-vitro-fertilized embryos, or to do prenatal testing and terminate affected pregnancies.

While more than 1,000 genes have been linked to recessive Mendelian disorders, the tests now available to prospective parents screen for only the most common, such as cystic fibrosis, and are mainly offered to parents in high-risk groups. Ashkenazi Jews are at particular risk of carrying Tay-Sachs mutations, for example.

“To be able to screen for more than 400 rare conditions is really an important advance,” says Eric Topol, director of the Scripps Translational Science Institute, who was not involved in the study. “We don’t have anything near that today.”

The major impediment to broad genetic screening has been cost, for the kind of DNA sequencing used in most clinical diagnostic tests is very expensive. Kingsmore and collaborators took advantage of the latest sequencing technology, which can sequence much greater volumes of DNA more quickly and cheaply. This technology has already transformed genetic research, but it has been slow to make its way into medical use.

“A huge question is whether it is robust enough to be used in clinical testing in humans,” says Kingsmore. According to his findings, published Wednesday in Science Translational Medicine, the answer is yes. When compared with another technology—microarrays designed to detect specific genetic mutations—the sequencing-based approach was 99.98 percent accurate. And follow-up testing of DNA from 100 people with a known mutation was 100 percent accurate. (Kingsmore’s team actually found that a number of the original samples had been misclassified.)

The advantage of a sequencing-based test over one that uses microarrays is that the latter can detect only known mutations. Sequencing, on the other hand, can spot any variation in disease-linked genes, even if it has never been seen before. (For some diseases, a few common mutations account for most cases of the disease, but for others, many different types of mutations can disrupt the relevant gene.) A comprehensive screening test launched last year by a startup called Counsyl tests only for known mutations. That’s a problem, says Kingsmore, because “we don’t have a good catalogue of mutations for most diseases.”

To develop the new test, the team modified existing technology to select relevant portions of the genome by binding stretches of complementary DNA to the regions of interest, drawing them out of a soup of DNA. Next they used sequencing technology from Illumina to analyze the extracted DNA. Since submitting their paper, the researchers have expanded the test to scan for mutations linked to more than 600 different conditions.

Kingsmore says the test currently costs $618 to run, not including any costs associated with commercialization. He predicts the cost will drop in next the next two years. His institute, a nonprofit that developed the technology with funding from a patient-advocacy group, aims to offer it for $500, on par with current carrier screens.

“Rapid progress in sequencing makes it possible to gather the enormous amount of sequencing information at a manageable cost,” says Arthur Beaudet, chair of the department of Molecular and Human Genetics at Baylor College of Medicine, who was not involved in the study. “And it will quite likely get cheaper over time.”

The test isn’t yet available to prospective parents. Researchers are now beginning to test the technology in clinical labs, a necessary step toward getting it approved by the Food and Drug Administration. “We believe we will be able to offer it on a research basis in the summer of 2011,” says Kingsmore.

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