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The Role of DNA testing in Diagnosis of MH Prospects and Pitfalls

By MHAUS President Henry Rosenberg, MD


Buyer of DNA testing Beware

In recent years, as DNA testing for diagnosis of many disorders has grown rapidly thanks to scientific advances, there has been a profusion of laboratories offering DNA testing to both the medical profession as well as the public. Although there are a few disorders where DNA testing of specific genes and specific mutations will predict susceptibility to a disorder, the problem for most inherited disorders is that all the DNA changes associated with the disorder have yet to be discovered. In medical parlance, DNA analysis for many conditions is specific, but not necessarily sensitive. That is if the patientâ??s gene manifests specific DNA changes then the patient will, with almost certainty, be at risk for the disorder. However, the complete list of DNA changes or mutations that are predisposed to most disorders are not known. For example, one of the better-studied disorders, Cystic Fibrosis (CF), DNA testing for a panel of over 100 known mutations will predict susceptibility with over 91% sensitivity (the ability to detect all those with the disorder). However, there are about 1500 mutations that may lead to some or all manifestations of cystic fibrosis and many appear only in a small fraction of those who develop Cystic Fibrosis. It would be extremely expensive and cumbersome to routinely screen for all the mutations. Since Cystic Fibrosis is inherited in a recessive manner (requires a mutation from each parent for the disorder to be manifest), when prospective parents are tested for determining the likelihood of their offspring having the disorder, someone with understanding of the complexities of genetic testing as well as the presentation of the disorder are necessary to provide best guidance to the patient. To add to the complexity, different ethnic groups will display different mutations that predict CF susceptibility. So someone who might not have Caucasian ancestry might not harbor the classic mutations predicting CF but have another mutation that was not part of the testing panel. Like most tests in medicine, the result of the test must be interpreted in the context of a whole variety of other factors.


Much of what I have described for CF pertains to the DNA diagnosis of MH but with even more uncertainty. As many of you know, mutations in one gene, the ryanodine receptor gene (RYR-1), a very large gene harbors hundreds of mutations that may be found in over 70% of patients and family members who are MH susceptible. However, it is still unclear which of these many genes really lead to changes in the protein structure of the cell that are responsible for the cellâ??s response to MH trigger agents and are manifest clinically as MH. To date only about 30 of over 300 mutations are specifically predictive for MH susceptibility. Undoubtedly, many of the other mutations are also â??causalâ?? for MH, but for many reasons, not the least of which is funding, scientists have not studied the ramifications of the DNA change. So when one of those that are not on the list of the 30 predictive mutations are found, it is denoted as indeterminate significance. In addition, we know that there are other genes and mutations that are associated with MH mutations, but scientists have not found all of them yet. Hence, as with CF, if a person has a DNA test for diagnosis of MH, that test requires interpretation by someone very familiar with the disorder , such as one of the MHAUS experts or a genetic counselor.


Interesting, yes, helpful, not really

All of this is background to what I wish to comment on in this blog. As some of you know, there are a variety of companies who advertise DNA testing â??directly to the consumerâ?? (i.e. the patient). In general, the patient pays a fee and sends a sputum sample to the lab, which usually costs a few hundred dollars and receives a report. The report usually contains wording such that the results require interpretation and the company cannot be held liable for mistakes in interpretation or analysis. When I sent in my sample to one of the companies, I received a report that I had a somewhat higher likelihood than the general population of developing a certain type of heart rhythm disturbance. But what does that mean? How should I change my lifestyle to reduce the chances of developing the problem? Should I take a certain medication? If so, which one? Should I undergo cardiac catheterization? Therefore, the report is almost meaningless because it is not actionable. Interesting, yes, helpful, not really.


Recently one of our experts submitted a sample to one of these commercial direct to consumer labs and got a report back that he was not MH susceptible. Why? Because he did not manifest one of the known MH mutations. However, he was not told whether his DNA contained other RYR1 mutations that have been associated with MH susceptibility but not proven to cause the syndrome as of yet. In other words, he was given, in my opinion, incomplete and perhaps misleading information. Just because a person does not have one of the causal MH mutations does not mean that s/he is NOT MH susceptible. DNA testing is specific but not terribly sensitive. We believe that the false positive rate on DNA testing is vanishingly low, but the false negative rate is significant. In fact the test result was not helpful to him and incomplete. Fortunately, he is very familiar with the MH syndrome and understood the results in context. Then I received an e-mail from a relative who also had his DNA analyzed by this company and was told he was not MH susceptible because he did not have one of the known mutations. I had to clarify the genetics and inheritance of MH for him.


So, if any of you have been told to obtain a DNA test for MH, please utilize one of the laboratories that are recommended by our experts, listed on our web site, or have your doctor determine how the laboratory does the test, who interprets the results and what experience they have with diagnosing MH. Of course the laboratory should be certified by one or more accreditation organizations such as CLIA


(Congress passed the Clinical Laboratory Improvement Amendments (CLIA) in 1988 establishing quality standards for all laboratory testing to ensure the accuracy, reliability and timeliness of patient test results regardless of where the test was performed. ) or the CAP (the College of American Pathologists), . Furthermore, either a genetic counselor or an expert in MH and MH-related disorders, should assist in test interpretation and advice on whom else in the family should be tested.


DNA testing holds great promise in detection and prevention of disease and abnormal drug reactions for the individual patient. Hence the term personalized medicine. However, although the technology of DNA analysis has advanced greatly such that the entire genetic makeup may be analyzed in detail for under $10,000, the problem now is the interpretation of the changes. This will require not only knowledge of the structure of a patientâ??s DNA, but also correlation of the DNA alteration with the disease states. This has lead to a rapidly expanding field called bioinformatics,â?? The use of computer science, mathematics, and information theory to model and analyze biological systems, especially systems involving genetic material.â??( http://www.thefreedictionary.com/bioinformatics).


Over the next number of years, we anticipate, although cannot guarantee that the DNA testing will become more sensitive and perhaps in the future lead to a screening test for MH susceptibility. Such analysis will also show the linkage between MH and a variety of other disorders.


As the story evolves, we intend for MHAUS to be â??theâ?? source of accurate information about MH and related syndromes.


Help us realize that ambition by becoming a member or contributor to MHAUS.


Thanks. As always, your comments are appreciated.


The opinions and information expressed in this blog do not necessarily represent those of MHAUS or itâ??s Professional Advisory Council or other experts.

This item filed in the following categories:
  • MH and MHAUS Updates
The mission of MHAUS is to promote optimum care and
scientific understanding of MH and related disorders.