When faced with diagnosing neuropathies, choosing which genetic test to use—or whether to order one at all—is complicated by a number of factors. This was the focus of a session at the 2017 meeting of the American Association of Neuromuscular and Electrodiagnostic Medicine. Chris Klein, MD, Professor of Neurology at the Mayo Clinic, addressed the factors that influence genetic testing for neuropathic disease.

Initially, Klein pointed out the differences and limitations of the various genetic tests.

Whole-Genome Testing and Whole-Exome Testing

Whole-genome testing sequences about three billion base pairs. This test is very expensive—about $2,500—and time-consuming.

The whole-exome test focuses on about 40 million base pairs, which amounts to about two percent of the genome. At $800, it is less costly than whole genome testing, but it’s still not cheap for most budgets.

Both of these tests cast a wide net, so they are bound to catch unintended targets. Rare genetic variants, of which we don’t yet understand the significance, are frequently discovered with these tests. Unexpected findings can also produce ethical dilemmas for the neurologist and patient.

For these reasons, Klein suggests a more selective approach to genetic testing is often warranted.

Targeted Gene Panel

A targeted gene panel will test around 2.5 million base pairs from around 100 to 200 genes. It costs roughly $150, making it far more affordable than the more comprehensive tests.  According to Klein, this approach can yield the most useful results when guided by patient phenotype and family history.

Specifically, the what, when, and where of the phenotype—an algorithmic approach—can provide the most important information for gene panel selection:

  • What are the symptoms? Does the patient have pain, sensory or motor issues?
  • Where are symptoms? Are they distal? Are they symmetric?
  • When did the symptoms appear? Were they sudden or gradual?

The clinician can compare these phenotypic characteristics to known pathological conditions in order to select a gene panel. The most useful results are found in testing for disease categories with significant genetic variations where a focused gene panel has a good shot at detection.

Disease categories where this approach is most useful include inherited:

  • Neuropathy
  • Myopathy
  • Neuromuscular junction disease
  • Motor neuron syndromes
  • Epilepsy syndromes

Further, the targeted gene panel is far less likely than whole-genome or -exome testing to find genetic variants of unknown significance. It’s also less likely to uncover genetic disorders that present ethical concerns for clinician and patient.

Klein explains that the targeted gene panel is most clinically beneficial in diagnosing many neurological conditions. While this may change rapidly in the fast-moving world of genetic medicine, today targeting offers the best results for diagnosing hereditary neuropathies.