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Misclassification of Benign Genetic Variants as Pathogenic Points to Need to Diversify Screening Populations, Neurogeneticists Say

Moran, Mark

doi: 10.1097/
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A study that found multiple minority patients had previously been given positive results for the risk for hypertrophic cardiomyopathy on the basis of genetic mutations subsequently known to be benign elicited discussion among neurogeneticists about the importance of sequencing more diverse populations.

The misclassification of benign genetic variants as pathogenic is common across all medical specialties, including neurology. But an August 18 paper in the New England Journal of Medicine has spurred new discussion about why that it is so and what can be done about it. Specifically, it points to the need for greater inclusion of diverse racial and ethnic populations in genomic studies.

The paper reported that multiple minority patients had previously been given positive results for the risk for hypertrophic cardiomyopathy on the basis of the presence of genetic mutations now known to be benign.

Isaac S. Kohane, MD, PhD, professor of pediatrics and health science technology at Harvard Medical School, and colleagues used publicly accessible exome data to identify variants that had previously been considered causal in hypertrophic cardiomyopathy and that are overrepresented in the general population. They studied these variants in diverse populations and reviewed patient records at a leading genetic-testing laboratory for analysis of these variants.

They found multiple patients, all of whom were of African or unspecified ancestry, who had received positive reports, with variants misclassified as pathogenic on the basis of the understanding at the time of testing. Subsequently, all reported variants were re-categorized as benign. The mutations that were most common in the general population were significantly more common among black Americans than among white Americans. Simulations showed that the inclusion of even small numbers of black Americans in control cohorts probably would have prevented these misclassifications.

Asked to comment on the article, several neurogeneticists told Neurology Today that a similar problem certainly applies to neurological disorders. “The increased use of genomic sequencing in patients with rare neurogenetic diseases has led to more frequent observation of variants previously reported as pathogenic in the pre-genomic era,” said Brent L. Fogel, MD, PhD, FAAN, director of the Neurogenetics Clinic at the University of California, Los Angeles (UCLA).

“An important concern is always whether such variants are simply benign alleles common to specific populations and, in the absence of genetic data from these diverse populations, we cannot know if such variants are truly pathogenic and risk misdiagnosing our patients,” he said. “Efforts to increase the diversity of sequencing data available for variant analysis are critical for accurate genetic diagnosis.”

Daniel Geschwind, MD, PhD, senior associate dean and associate vice chancellor of precision health at UCLA, agreed. “That is why we are now focusing on African-American recruitment for our autism genetic studies. It's an enormous public health issue.”

Other genetic research centers have taken up the cause of expanding awareness about the importance of genetics in personal, family, and community health to minority communities. For instance, the University of Miami's John P. Hussman Institute for Human Genomics initiated the Genetics Awareness Project to inform South Florida's black and Hispanic communities about the value of genetics and to actively promote awareness, interest, and involvement in genetics among people in those communities.

Jeffery M. Vance, MD, PhD, director of the Center for Genomic Education and Outreach at the Hussman Institute, reported that the group has led three conferences in Miami, San Francisco, and Washington, DC, around the theme, “Why We Can't Wait: Conference to Eliminate Health Disparities in Genomic Medicine.” A fourth conference is scheduled for the Spring of 2017.

“I think the NEJM article emphasizes that we indeed can't wait to address this growing problem,” Dr. Vance said. “Education on the importance of extending the opportunities that genomic medicine presents to all of society requires partnership at all the levels of health care. This includes not only the communities involved, but also health providers and health payers.”

Stefan M. Pulst, MD, FAAN, professor and chair of the department of neurology at the University of Utah and editor of Neurology: Genetics, said that in the areas of neuropathy and movement disorders there are variants that were reported ten or fifteen years ago as pathogenic that are now known to be benign. “This was not bad science, it was just what we knew at the time,” he said.

“The problem of erroneously assigning mutation status to rare, sometimes population-dependent benign DNA variants is widespread,” Dr. Pulst said. “It is of most actionable importance in the clinical arena, but as editor of Neurology: Genetics, my associate editors and I face similar challenges when deciding on the acceptance of manuscripts reporting novel mutations in established disease-causing genes.”

He cited another way in which the problem of misclassification can impact routine clinical encounters. “Patients are referred to me by a physician for neurogenetic counseling with regard to a disease-causing mutation,” he said. “After review of the DNA variant I often have to tell them that the DNA change is just a rare variant of unknown significance. The patients are disappointed and often upset because they ‘lost’ their diagnosis after a long and exhausting search for a name of their illness.”

Dr. Pulst noted that commercial laboratories doing genomic research are typically quite careful to label rare polymorphisms as “variant of uncertain significance (VUS).”

To career geneticists, VUS is understood to mean what it says — that the variant may or may not be associated with disease. But that may not be so clear to patients and to some clinicians, he said.

Perhaps the largest lesson gleaned about genomics since the beginning of the genetic age is the vast variability of the human genome — unimagined when the Human Genome Project began, and perhaps difficult to grasp for those not closely attuned to genomic research.

“To geneticists, the possibility of misclassifying rare variants is common information and a large problem, but patients and some clinicians are liable to read about a genetic variant — even one classified as of uncertain significance — and assume that it is probably pathogenic,” Dr. Pulst said. “The reason is that most people, apart from geneticists, simply don't appreciate the enormous variation in genomes.”

Dr. Vance added: “Education on all levels is falling behind the technology and health disparity in the groups contributing to the genetic databases compounds the problem. Currently in our clinical evaluations we only use the 2 percent of the genome that codes for protein. We are now actively researching the contributions of genetic variants in the remaining 98 percent of the non-protein coding genome, which is much more variable. We need to get these problems addressed before this additional wealth of genomic data comes into the clinic.”

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In 2015, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology published revised standards and guidelines for the interpretation of sequence variants in the journal Nature.

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“Our understanding of the clinical significance of any given sequence variant falls along a gradient, ranging from those in which the variant is almost certainly pathogenic for a disorder to those that are almost certainly benign,” the guidelines read.

The joint consensus report recommended the use of specific standard terminology to describe variants identified in genes that cause Mendelian disorders. Those terms are “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign.” The joint statement also described a process for classifying variants into those five categories based on criteria using typical types of variant evidence — population data, computational data, functional data, or segregation data.

The guidelines also include specific advice for clinicians on how to use genetic testing in medical management decisions. “Variant analysis is, at present, imperfect, and the variant category reported does not imply 100% certainty,” according to the joint statement. “In general, a variant classified as pathogenic using the proposed classification scheme has met criteria informed by empirical data such that a health-care provider can use the molecular testing information in clinical decision making. Efforts should be made to avoid using this as the sole evidence of Mendelian disease; it should be used in conjunction with other clinical information when possible....A variant of uncertain significance should not be used in clinical decision making.

“A variant considered likely benign has sufficient evidence that a health-care provider can conclude that it is not the cause of the patient's disorder when combined with other information, for example, if the variant does not segregate in an affected family member and complex inheritance patterns are unlikely. A variant considered benign has sufficient evidence that a health-care provider can conclude that it is not the cause of the patient's disorder.”

Mark Moran

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•. Manrai AK, Funke BH, Rehm HL, et al. Genetic misdiagnoses and the potential for health disparities N Engl J Med 2016: 375(7): 655–665.
•. Richards S, Aziz N, Bale S, et al.on behalf of the ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Genet Med 2015; 17:405–423.
© 2016 American Academy of Neurology