Children who undergo expansive genetic sequencing may not be getting the thorough DNA analysis their parents were expecting, say experts at UT Southwestern Medical Center.
A review of clinical tests from three major U.S. laboratories 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 reanalysis by UT Southwestern shows each lab on average adequately examined less than three-quarters of the genes - 34, 66, and 69 percent coverage - and had startlingly wide gaps in their ability to detect specific disorders.
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.
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." Jason Park, M.D., Ph.D., associate professor of pathology at UT Southwestern
Whole exome sequencing, a technique for analyzing protein-producing genes, is increasingly used in health care to identify genetic mutations that cause disease - mostly in children but also in adults with rare or undiagnosed diseases. However, 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 new 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 - 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.
Notably, 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. Related Stories
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