Hack sequencing
Some methods of reading DNA skip entire "pages"
A recheck of genetic tests from three major laboratories in the United States has shown that full-exome sequencing (reading only protein-coding genes) can miss large fragments of DNA. Because of this, clinicians can leave up to half of patients without a correct diagnosis, be it cancer or epilepsy, the researchers said on the pages of Clinical Chemistry (Baudhuin et al., Predictive and Precision Medicine with Genomic Data).
Today, medicine is turning to genetic tests more and more often: for example, they help to exclude a diagnosis in children, learn about the risk of developing diseases or how to change the lifestyle in order to suffer less from their symptoms. Scientists from the University of Texas Southwestern Medical Center rechecked genetic tests in 36 patients from national American laboratories for 2012-2016 and found that they analyzed only 36%, 66% and 69% of the genes.
Most often, such gaps appear not because of deception of customers, but because of imperfection of sequencing methods. Today we cannot untangle a tightly packed DNA molecule and read it all at once. To avoid mistakes and not to confuse the sequence of fragments during assembly, the same sequence should be counted at least several dozen times (at least for commercial companies – 20) and superimposed on each other. Geneticists call this "coverage", and if it is not enough, then the sequence section is not read clearly enough. But therapists usually have no idea about these restrictions, and companies can use it.
"Many patients are young children with neurological disorders, and they need the most complete diagnostic test," explains Jason Park, Ph.D. and associate professor of pathology at the University of Texas Southwestern Medical Center. – The whole system falls apart when you start thinking about these tests to rule out a diagnosis. The negative result of exome sequencing makes no difference when so many genes are left without careful analysis."
So, in the case of epilepsy, one of the laboratories in some tests missed up to 80% of the genes associated with the disease, the second analyzed 40%, and only one analyzed at least three quarters properly. Only 1.5% of all protein-coding genes were analyzed in all 36 samples. In the rest, large fragments were skipped, and in all cases different. In one of the laboratories, 27% of the genes in all tests were well–coated, in another - 28%, and in the third only 5%.
"When we saw these data, we made it mandatory for laboratories to ask about covering specific genes," comments co–author Garrett Gotway, Ph.D. and clinical geneticist at the University of Texas. "I don't think it's worth hoping for full coverage of all 18,000 genes every time, but it's fair to expect at least 90%." According to her, to clarify the diagnosis, it is better to rely not on full-genome or full-exome, but on more narrowly targeted sequencing, checking only those genes in which mutations are likely to be important in a particular case. Otherwise, there is a risk of missing the most important thing, trying to cover everything at once.
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