New Study Reveals Most Commercial Lab Conducting Genetic Sequencing Tests Routinely Fail to Analyze Large Segments of DNA, Hence Lacking Accuracy
Source: Thailand Medical News Jan 07, 2020 4 years, 3 months, 2 weeks, 5 days, 8 hours, 3 minutes ago
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.
Genetic 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 show
ed 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 
