• Posted March 10, 2022

Science Brings Shortcut to Spotting 50 Rare Genetic Diseases

Scientists have developed a single test that can rapidly detect a collection of rare genetic diseases -- an advance they hope will shorten the "diagnostic odyssey" that people with these conditions can face.

The test diagnoses conditions known collectively as "STR-expansion" disorders, which include more than 50 genetic diseases that affect the brain, nervous system and muscles.

Some of the better known are Huntington's disease and Fragile X syndrome, but there are many others -- often with overlapping signs and symptoms that make them tough to distinguish.

They include, among others, inherited ataxias, which gradually impair a person's hand coordination, speech and ability to walk; myotonic dystrophies, which cause progressive weakness in the muscles that move the body, and sometimes the heart and muscles involved in breathing and digestion; and inherited myoclonic epilepsies -- seizure disorders that cause the body muscles to contract and "jerk."

Right now, testing for STR-expansion disorders is "hit or miss," said researcher Dr. Kishore Kumar, of the Garvan Institute of Medical Research in Sydney, Australia.

"When patients present with symptoms, it can be difficult to tell which of these 50-plus genetic expansions they might have, so their doctor must decide which genes to test for based on the person's symptoms and family history," Kumar said in an institute statement.

For some, he said, that can lead to a years-long "odyssey" of testing to get an answer.

Enter the new test, based on nanopore technology, which allows rapid "reads" of long stretches of DNA. That's key in diagnosing STR-expansion disorders because the conditions involve abnormally long "repeats" in the chemical letters that make up DNA.

In a study of 25 patients with known STR-expansion disorders, Kumar and his colleagues found that the test correctly diagnosed all of them.

The goal, the researchers said, is to make the test available for everyday practice in the next two to five years.

The findings were published online March 4 in the journal Science Advances.

"This is significant," said Dr. Hui Zhang, a geneticist at Yale School of Medicine who was not involved in the research.

The ability of the test to do "long reads" of DNA, she said, is the key piece.

Right now, Zhang said, the process of testing for STR-expansion disorders one by one is time-consuming and can become very expensive.

There are "next-generation" genetic testing techniques, including whole-genome and whole-exome sequencing. Whole-genome sequencing scours all of a person's DNA to try to identify disease-causing mutations; whole-exome sequencing focuses on the portion of a person's DNA that contains instructions for making proteins.

But, Zhang explained, those techniques do "short reads" (looking at shorter lengths of DNA), which means they miss the very long letter repeats that mark STR-expansion disorders.

"This [new test] is complementary to short reads -- it fills in a blank," Zhang said.

Heidi Rehm is vice president of laboratory genetics at the American College of Medical Genetics and Genomics, and a professor of pathology at Massachusetts General Hospital in Boston.

Rehm said that getting a genetic diagnosis -- for STR-expansion disorders or any rare disease -- is critical not only for the person with the disorder, but for the family, too.

The new test is a good one, Rehm said. The broader questions relate to how it could eventually be incorporated into real-world practice.

It's not clear, for example, if it should be a stand-alone test, Rehm said, or done as part of whole-genome or whole-exome sequencing.

There is also the question of cost, Rehm said, which could be an obstacle for labs in adopting the test.

According to Kumar's team, the nanopore sequencing device is the size of a stapler and costs around $1,000.

But there is also the cost of the sequencing and analysis, Zhang said, which is unclear.

She also noted there will be cases where the new test could be "too big" -- if symptoms and family history point to a likely culprit, and traditional testing can be done.

STR-expansion disorders cannot be cured. But a quicker diagnosis can help doctors detect and treat the various complications these conditions can cause, Kumar's team said.

More information

The U.S. National Institutes of Health has more on rare disease diagnosis.

SOURCES: Heidi Rehm, PhD, vice president, laboratory genetics and member, board of directors, American College of Medical Genetics and Genomics, Bethesda, Md., and professor, pathology, Massachusetts General Hospital, Boston; Hui Zhang, MD, PhD, associate professor, genetics and pediatrics, co-director, DNA Diagnostic Lab, Yale School of Medicine, New Haven, Conn.; Garvan Institute of Medical Research, news release, March 4, 2022; Science Advances, March 4, 2022, online