Once strictly the domain of research labs, tests that sequence large swaths of the human genome called the exome have become increasingly popular among medical specialists as a way to understand the genetic causes of rare disease.
However, a sampling of a dozen tests from each of three commercial laboratories has found they often fail to adequately analyze large segments of DNA that could be contributing to disease, researchers report this week in the journal Clinical Chemistry.
Sequencing exomes can help solve complex cases, and the tests have become a fairly common tool when doctors suspect a genetic mutation could be causing rare or undiagnosed disease, especially in children, Dr. Garrett Gotway said in a telephone interview.
Exome sequencing tests look only at the segments of DNA known as exons that contain instructions for making proteins. While exons represent just 2 percent of the whole genome, they contain some 85 percent of gene variations associated with disease.
According to the researchers, about half of these tests come up negative.
For the current study, Gotway, a clinical geneticist at UT Southwestern in Dallas, Texas, and colleagues reanalyzed tests performed between 2012 and 2016 at three commercial labs. They found that on average, based on accepted industry standards, each lab adequately analyzed only three-quarters of the genes tested.
Less than 1.5% of the genes were completely analyzed in all 36 samples, and there was wide variation among the labs. An analysis of the 12 tests from one lab, for example, showed that 28% of the genes were never adequately analyzed.
“Many of the physicians who order these tests don’t know this is happening,” coauthor Dr. Jason Park, an associate professor of pathology at UT Southwestern, said in a statement.
Park said parents of young children with serious disease want their children to have the most complete diagnostic test possible. “But they don’t realize whole exome sequencing may miss something that a more targeted genetic test would find,” he said.
Heidi Rehm, medical director of the Clinical Research Sequencing lab at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, who was not involved with the study, said assessing the quality of exome tests on the market is important to ensure that patients are getting high-quality tests.