Study: Exome-sequencing has limited ability to diagnose limb-girdle muscular dystrophy

As medical technology advances, it can be tempting to assume that new genetic tools can accurately diagnose anything — but that’s not always the case. A University of Florida researcher has found that one type of genetic test may not be able to identify a particular type of muscular dystrophy, leaving patients with this disease at risk of going undiagnosed if they only receive this kind of testing.

University of Florida Genetics Institute member Peter B. Kang, M.D., examined the efficacy of exome sequencing in identifying pathogenic mutations for limb-girdle muscular dystrophy, or LGMD, in a paper published in October in the Journal of Human Genetics. It was the largest study of its kind focusing on patients in the United States with this disease, which causes muscle weakness, particularly in the shoulders and hips.

“I think there are a lot of questions, both among researchers and clinicians, about the best use of new technologies like exome sequencing,” said Kang, chief of the division of pediatric neurology in the department of pediatrics and an associate professor of pediatrics. “In the current study, we focused on mutations that we found in genes that had already been associated with muscle diseases.”

Exome sequencing is a type of next-generation sequencing. Whereas next-generation sequencing generates massive amounts of genetic data simultaneously, exome sequencing is used specifically to search only for coding regions of genes that contain the codes to make proteins. While exome sequencing generates less data than full genome sequencing, making it simpler to process and interpret, this type of sequencing also creates the opportunity to miss mutations.

The study involved a group of patients who had all been clinically diagnosed with LGMD. The researchers identified mutations in multiple genes associated with muscle disease. Less than half, or 40 percent, were diagnosed using exome sequencing.

“Exome sequencing is a powerful technology, but it’s not the be-all and end-all of genetic diagnosis,” Kang said.

Despite some shortcomings the technology did provide the researchers with additional information. Kang said they found LGMD mutations in several genes not traditionally associated with the disease.

“The implication for clinical testing is that these patients, when they get clinical genetic testing, should really have access to broad sequencing panels, not just the classic LGMD genes,” Kang said.

Kang has a word of advice for clinical labs setting up targeted captured sequence panels for diseases such as LGMD. He suggests they be as broad as possible, as Kang’s group found mutations in genes where they didn’t expect them.

“I think this is good for people in both the research and clinical setting to know about when they’re looking for mutations in these types of patients,” he said. “I think it’s very useful, especially for people in the United States, because then they know to cast a wide net.”