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Over the past five years, the molecular tools and our computing power have improved drastically leading to increased diagnosis of rare disease with the use of noninvasive gene testing. Currently, the most advanced genetic tool is whole exome sequencing (WES). While extremely useful, there are other tests that should be considered before and by the physician ordering an exome test.
Exome sequencing analyzes approximately 3 to 4% of our genetic code, specifically all the protein-encoding genes. So while extensive and a giant leap forward, there is a limit to the science and the result is not 100% definitive. Approximately 75 to 85% of disease causing mutations are purported to be detected by exome sequencing.
Since becoming clinically available several years ago, we have utilized this tool in our patient population for ongoing evaluation of their underlying clinical problems. Our position, particularly with insurance companies who strive to deny patient access to advanced testing through coverage denial, is that such testing leads to accurate diagnosis, implementation of appropriate treatment, valuable recurrence risk information, and prevention of ongoing testing.
A recent study by Soden et al published in 2014, supports our position. In this study, whole exome sequencing identified disease causing mutations in 45% of 119 children with previously undiagnosed neurodevelopmental conditions. In addition, the results of genomic sequencing lead to a change in diagnosis and in medical care for approximately 49% of the children.
We have examples of many patients, particularly children, with complex histories who remained undiagnosed or who were thought to have a mitochondrial disease until completion of genomic sequencing. Some of these children had de novo mutations indicating that neither parent were carriers and, as such, faced no recurrence risks for subsequent pregnancies. Others were found to have gene changes associated with an alteration in treatment plan including the re-diagnosis of presumed mitochondrial patients (based on muscle biopsy results) with other disorders that required no yearly screening or intervention because they were static encephalopathies. While the human factor is most important, the Soden study also supports our supposition that utilizing exome sequencing in certain cases is a cost-effective approach from a financial perspective as well.
Despite its clear utility, the patient population must be aware of several factors in regards to the ordering and interpretation of exome sequencing. Because the test is costly, upwards of $10,000 per genomic sequence, hospital systems often deny or limit access to the testing because their reimbursement rate through insurance companies is so low that they incur an out-of-pocket expense when paying the laboratory that provides the testing. As such, many institutions have resorted to a process whereby exome sequencing must be approved by a panel before being completed through their hospital system. This leaves well-qualified clinicians with no recourse in regards to evaluating their patients unless their plan is approved by panels often consisting of pathologists who have no real knowledge of genetic disorders. Therefore, gaining access to exome sequencing through certain hospital systems can be problematic or impossible. In our particular practice, we are able to bypass these difficulties and the laboratory performing the testing circumvents the "middlemen" by working directly with a patient’s insurance to gain coverage for the study.
The second major hurdle in regards to exome sequencing is the interpretation of the data since a lab does not diagnosis a patient. A clinician who understands the clinical presentation of the patient and who understands the significance of the exome results correlates the two into a diagnosis. Some insurance companies have started the requirement that at least a genetic counselor or geneticist must approve the testing before it will be covered by insurance. Sometimes, the data is clear and easily digested by ordering practitioners but often it is complex. Many genomic profiles identify "variants of unknown significance" which requires extensive review of literature and considerable thought in regards to its implications for a given patient and his or her family. As such, such testing MUST be reviewed in a patient appointment by a qualified provider such as a geneticist to prevent misinterpretation of the data.
A case in point is that of a young woman on whom we identified a variant of unknown significance in a gene inherited from her father associated with a distal myopathy. The causality of that variant was only determined after an extensive discussion in an appointment with the young woman and her parents which determined her father indeed also had a distal myopathy, albeit more mild in presentation. A quick review of only the data by someone other than a qualified provider most likely would have led to a misinterpretation of the results and failure to recognize the causality of this gene change for this woman's disease process.
In summary, exome sequencing is a very powerful tool in the hands of an expert in the evaluation of complex cases but it is expensive and Insurance coverage can be difficult to secure in certain environments. If overused inappropriately we foresee patients truly in need of this advanced testing facing significant hardships to gain access to the testing through approvals and/or coverage. In addition, the interpretation of the data and its implications for the patient and his or her extended family requires a sophisticated knowledge of genetics and the algorithms and databases used to analyze the data and interpret the results. As such, patients are best served by obtaining evaluation through a provider that specializes in the disease process they are concerned about and who can help them navigate the complexities of this advanced genomic sequencing.
Fran Kendall, M.D.
This post is not meant to be a recommendation or a substitute for professional advice and services rendered by qualified doctors, allied medical personnel, and other professional services. The responsibility for any use of this information, or for proper medical treatment, rests with you.