New Study Reveals Most Commercial Lab Conducting Genetic Sequencing Tests Routinely Fail to Analyze Large Segments of DNA, Hence Lacking Accuracy
New Study Reveals Most Commercial Labs Conducting Genetic Sequencing Tests
Routinely Fail to Analyze Large Segments of DNA, Hence Lacking Accuracy
A review of clinical tests from three major U.S. laboratories by UT Southwestern Medical Center experts shows whole exome sequencing
routinely fails to adequately analyze large segments of DNA, a potentially critical deficiency that can prevent doctors from accurately
diagnosing potential genetic disorders
, from epilepsy to cancer.
The UT Southwestern reanalysis shows each lab on average adequately examined less than three-quarters of the genes
ie 34, 66, and 69 percent coverage and had startlingly wide gaps in their ability to detect specific disorders.
The researchers say they conducted the study because they believe vast differences in testing quality are endemic in clinical genetic sequencing
but have not been well documented or shared with clinicians.
Dr Jason Park, M.D., Ph.D., Associate Professor of Pathology at UT Southwestern told Thailand Medical
News, “Many of the physicians who order these tests don’t know this is happening. 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.”
Currently, whole exome sequencing
, a technique for analyzing protein-producing genes
, is increasingly used in healthcare
to identify genetic
mutations that cause disease mostly in children but also in adults with rare or undiagnosed diseases.
However, Dr Park says the process of fully analyzing the approximately 18,000 genes
in an exome
is inherently difficult and prone to oversights. About half the tests do not pinpoint a mutation.
The recent study published in Clinical Chemistry
gives insight into why some analyses may be coming back negative.
researchers re-analyzed 36 patients’ exome
tests conducted between 2012 and 2016 ie 12 from each of the three national clinical laboratories and found starkly contrasting results and inconsistency with which genes
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.
Significantly, less than 1.5 percent of the genes
were completely analyzed in all 36 samples. A review of one lab’s tests showed 28 percent of the genes
were never adequately examined and only 5 percent were always covered. Another lab consistently covered 27 percent of the genes
Dr Park added, “And things really start to fall apart when you start thinking about using these tests to rule out a disease. A negative exome
result is meaningless when so many of the genes
are not thoroughly analyzed.”
For instance, the chances of detecting an epileptic disorder from any of the 36 tests varied widely depending on which genes
were analyzed. One lab conducted several patient tests that fully examined more than three quarters of the genes
associated with epilepsy, but the same lab 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.
Dr Garrett Gotway, M.D., Ph.D., a clinical geneticist
at UT Southwestern who is the corresponding author of the study commented,“When we saw this data we made it a regular practice to ask the labs about coverage of specific genes
. 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.”
The study findings build upon previous research that showed similar gaps and disparities in whole genome sequencing
, a technique that examines all types of genes
, regardless of whether they produce proteins.
Dr Gotway says he hopes the findings will prompt more physicians to ask labs about which genes were covered and push for improved consistency in testing quality. He also encourages physicians even before ordering the test to consider whether whole exome sequencing
is the best approach for the patient.
Dr Gotway added, “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. 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.”
Dr Gotway suggests that in those cases, ordering a smaller genetic
test that completely analyzes a panel of genes
associated with that disease. He says they’re less expensive and just as likely to help physicians find answers.
Dr Park is medical director of the Advanced Diagnostics Laboratory at Children’s Medical Center Dallas. Gotway is assistant professor of pediatrics and internal medicine. Both are members of UT Southwestern’s Eugene McDermott Center for Human Growth and Development.
Reference: Garrett Gotway, Eric Crossley, Julia Kozlitina, Chao Xing, Judy Fan, Callie Hornbuckle, Jenny Thies, Donnice Michel, Christine Quinn, Angela E Scheuerle, Luis A Umana, Crescenda L Uhles, Jason Y Park, Clinical Exome Studies Have Inconsistent Coverage, Clinical Chemistry, Volume 66, Issue 1, January 2020, Pages 199–206, https://doi.org/10.1093/clinchem.2019.306795