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VBCN - May 2015 Volume 2, No 1 - Personalized Medicine in Neurology
Chase Doyle

Washington, DC––In a series of debates at the 2015 annual meeting of the American Academy of Neurology, expert physicians addressed current and controversial issues in neuroscience. In the following debate, Christine Klein, MD, Institute of Neurogenetics, University of Lübeck, Germany, advocated the merits of whole-exome sequencing, whereas Claes Wahlestedt, MD, PhD, Leonard M. Miller Professor and Associate Dean, University of Miami, FL, argued that there are limited examples of actionable findings to support whole-exome sequencing testing.

Whole-Exome Sequencing for Diagnosis of Rare Diseases

In framing her stance, Dr Klein proposed that neurologists are uniquely positioned to capture the value of whole-exome sequencing.

“Inherited conditions are, by definition, rare,” began Dr Klein, “but there are thousands in neurology. In the United States alone, about 1 in 10 people suffer from a rare disease.”

In a process known as reverse phenotyping, whole-exome sequencing reveals the entire spectrum of mutations present in the exome, which can then be correlated with the phenotypic features of each individual patient.

“This means that the genetic finding brings you back to the clinical and informs it,” Dr Klein explained, “and, indeed, diagnoses have even been revised based on genetic findings.”

Citing the recent “Rare Diseases” report by the European Commission, Dr Klein shared that 30% of patients with rare diseases were initially misdiagnosed, enduring an average of 5 to 30 years of diagnostic delay. Whole-exome sequencing is effective and accurate; a recently published study demonstrated that the use of whole-exome sequencing more than tripled the rate of clarification of patients with unknown ataxias compared with next-generation sequencing panels.

“All of this has a great impact on our patients in terms of an earlier and correct diagnosis,” Dr Klein observed.

Although Dr Klein acknowledged that whole-exome sequencing is by far the most expensive test when compared with single-gene tests and targeted gene panels, she noted that the price of whole-exome sequencing can be misleading. “It is only the most expensive at first,” she clarified. “Single-gene tests and even gene panel tests are often ordered more than once for an individual patient, raising the costs considerably.”

Encouraging conversations between geneticists, genetic counselors, molecular biologists, informaticians, and neurologists, Dr Klein emphasized the role of the latter: “It should be neurologists taking the lead for our patients, expanding horizons of diagnosis and disease pathogenesis,” she said.

Whole exome-sequencing may also help to reduce healthcare costs for payers.

“Sequencing costs have been plummeting over the past few years, and it’s important to note that [whole-exome sequencing] is a once-in-a-lifetime diagnostic test. It’s minimally invasive; it’s relatively inexpensive; and, this is a very unique feature: it will become even more informative over time as clinical and genetic databases and our knowledge improve,” Dr Klein concluded.

Sequencing Not Ready for Clinical Use in Neurology


Dr Wahlestedt argued that whole-exome sequencing is still largely in the realm of research, an expertise more suited for medical geneticists than for neurologists.

“[Whole-exome sequencing] plays a valuable role in research, including neurodegenerative disease gene discovery, and can be done in any research project,” Dr Wahlestedt explained. Its valuable potential for discovery notwithstanding, Dr Wahlestedt remained unconvinced of its present clinical utility.

“There are still no first-line tests in neurology or any other field for that matter,” he said. “Higher suspicion of genetic condition––including autism disorders and epilepsy––is what usually goes along with a positive result.”

In addition to the limitations of whole-exome sequencing attributed to the complexity of the genome, Dr Wahlestedt also noted several ethical considerations, including whether patients should have access to their sequencing results and whether this information should be shared with insurance companies. Whole-exome sequencing’s main limitation, Dr Wahlestedt said, is the reality that exome findings are rarely actionable.

“Even in cancer, we have hundreds of drug treatments already available and should be guided by genomics, but that’s not necessarily the case….The vast majority of tumors still don’t correlate with exact targets,” he said, explaining that despite the availability of targeted treatments, 60% of surveyed US oncologists do not base their treatment decision on patients’ genetic mutation subtype. “Technology is a wonderful thing, but [whole-exome sequencing] is still in the realm of research. Genetics, to this day and age, rarely guides treatment. We are not quite at the level of precision medicine where we want to be.”

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