Gaps in Whole Genome Sequencing Tests Could Hinder Disease Diagnosis

January 06, 2020 - A review of clinical tests from three major US laboratories showed that whole genome sequencing tests routinely fail to adequately analyze more than a quarter of genes, which may prevent providers from detecting potential genetic disorders.

Whole genome sequencing is a technique used to identify genetic mutations that cause disease, mostly in children but also in adults with rare or undiagnosed disorders. However, because the process of fully analyzing the nearly 18,000 genes in an exome is a challenging, error-prone task, about half of the tests don’t identify a mutation.

Researchers from UT Southwestern re-analyzed 36 patients’ exome tests conducted between 2012 and 2016, twelve from each of the three national clinical laboratories.

The team looked through the tests to find the percentage of genes that were completely analyzed. A gene was not considered completely analyzed unless the lab met an industry-accepted threshold for adequate analysis of all DNA that encodes protein, which is defined as sequencing that segment at least 20 times per test.

The results showed that less than 1.5 percent of the genes were completely analyzed in all 36 samples. A review of one lab’s tests showed that 28 percent of the genes were never adequately analyzed and only five percent were always covered. Another lab consistently covered 27 percent of the genes.

"Many of the physicians who order these tests don't know this is happening," said Jason Park, MD, PhD, associate professor of pathology at UT Southwestern. "Many of their patients are young kids with neurological disorders, and they want to get the most complete diagnostic test. But they don't realize whole exome sequencing may miss something that a more targeted genetic test would find."

Researchers noted that the chances of detecting an epileptic disorder from any of the 36 tests varied widely depending on which genes were analyzed.

In one lab, scientists conducted several patient tests that fully examined more than three quarters of the genes associated with epilepsy, but the same lab also had three other patient samples in which less than 40 percent were completely analyzed. Three tests from another lab came in at under 20 percent.

"Things really start to fall apart when you start thinking about using these tests to rule out a disease," Park said. "A negative exome result is meaningless when so many of the genes are not thoroughly analyzed."

The team expects that these findings will help more physicians ask labs about which genes were covered and push for improved consistency in testing.

"When we saw this data, we made it a regular practice to ask the labs about coverage of specific genes," said Garrett Gotway, MD, PhD, a clinical geneticist at UT Southwestern who is the corresponding author of the study. "I don't think you can expect complete coverage of 18,000 genes every time, but it's fair to expect 90 percent or more."

Additionally, researchers noted that providers should consider whether whole exome sequencing is the best approach for the patient. If not, the team recommended that physicians order a smaller genetic test that completely analyzes a panel of genes associated with that disease.

"Clinical exomes can be helpful in complex cases, but you probably don't need one if a kid has epilepsy and doesn't have other complicating clinical problems," Gotway said. "There's a decent chance the exome test will come back negative and the parents are still left wondering about the genetic basis for their child's disease."