New Forms of Genetic Testing Improve Diagnosis, Raise Questions

“Knowing, if not all, is almost all,” said Matthew Harms, a neurologist and neurophysiologist from Washington University in St. Louis, in his presentation on genetic testing for neuromuscular disorders at the 2014 MDA Clinical Conference, held in Chicago March 16-19.

“Molecular diagnosis matters,” Harms said. “We must come to molecular diagnosis as the availability of molecularly based treatments increases.” He said genetic (also called “DNA-based,” or “molecular”) diagnosis brings closure to families and “names the enemy they are fighting.”

However, he said, new types of genetic testing also make genetic counseling more complicated; require that professionals learn more about the implications of each genetic mutation they identify in patients; raise questions about what to do with unexpected, or “incidental,” findings not related to the initial diagnostic process; and may not detect all disease-causing mutations.

Current approaches to genetic diagnosis, Harms explained, are based on a directed search for possible or probable genetic mutations that doctors believe could underlie the signs and symptoms they see in a patient through taking a history and conducting a physical examination and non-genetic tests, such as those measuring the speed and strength of nerve-to-muscle signals. This is a useful approach, Harms said, but one that “often falls short.”

To illustrate his point, he described a patient who was thought to have type 2 Charcot-Marie-Tooth disease but in whom no molecular diagnosis could be made after extensive testing for the known mutations for this condition. Ultimately, the patient underwent a new type of testing known as exome sequencing, in which all exons — the parts of the human genome that directly code for proteins — were examined. Two mutations were found in a gene underlying a rare neuromuscular disorder that had not originally been on the list of suspected conditions.

Exome sequencing can now be done for about $900, Harms said, which is considered affordable in many settings. However, it has limitations, Harms cautioned. It does not, for instance, find potentially significant mutations that are in introns, the parts of genes between exons that do not directly code for proteins. Nor does it find abnormally expanded sections of DNA, such as those that cause type 1 myotonic dystrophy (MMD1, or DM1) and one form of amyotrophic lateral sclerosis (ALS); or variations in the number of copies of a gene, an important factor in predicting the likely severity of spinal muscular atrophy (SMA).

We are on the threshold of newer forms of sequencing that can routinely examine the entire genome — genome sequencing — Harms said. This strategy, rapidly evolving so that it can be used more broadly than it is now, can detect more types of mutations but will be expensive.

Need to raise ‘genetic literacy’

Harms said that forms of genetic testing that scan entire genomes or exomes have already taught us to question our assumptions about genetic disorders and that newer forms of testing will be even more challenging. We have already learned, he said, that symptoms that can arise from a particular genetic mutation are much broader than had been anticipated; that there are more genes out there that cause disease than had been thought; that patients with multiple disease-causing mutations are not as rare as has been believed; and that understanding of genetics, even by professionals, is incomplete.

Mutations that are thought to be harmful sometimes turn out not to be, he said; while those that are thought not be harmful sometimes are. “Clarity will only come from collaboration as physicians,” he said. “Genomic literacy has to be raised, in ourselves and in our patients.”

Panel discussion raised questions

A lively panel discussion followed Harms’ presentation. In addition to Harms, the panel included geneticist Madhuri Hegde, a geneticist and MDA research grantee at Emory University in Atlanta; Carly Siskind, a genetic counselor at Stanford (Calif.) University; and neurologist Jerry Mendell, a longtime MDA research grantee and co-director of the MDA Clinic at Nationwide Children’s Hospital in Columbus, Ohio.

Among the important questions raised by this panel and by the audience included:

  • How should information that is found in genome or exome sequencing that does not relate to diagnosis of the sought-after neuromuscular disorder be handled? Should it be relayed to the family?
  • How should information of unknown significance be handled?
  • Since many more genetic mutations will be identified using newer methods than earlier approaches, will many people be barred from obtaining life insurance or long-term care insurance? Does this need to be considered when molecular diagnostic testing is ordered?
  • Is it in the best interests of a child who does not yet have symptoms of a genetic disorder to carry the label of a genetic disorder?
  • Testing DNA from a particular tissue, such as blood or saliva, may not give information about DNA variations found in other tissues, which is known to occur and to have significance in some neuromuscular disorders. How does one deal with that “murky” situation?
  • How do we deal with the shortage of genetic counselors now in practice?

None of these questions has a clear answer, although there seemed to be consensus that we need clear consent forms for patients and their parents; that we need more genetic counselors; that the level of knowledge of genetics and its role in disease must be raised for all professionals who are involved with patients; and that cost-benefit calculations must be made for genetic testing.

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