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Lack of Diversity in Genetic Studies Can Lead to Misdiagnoses

NEW YORK (GenomeWeb) – Patients of African or unspecified ancestry received misdiagnoses of hypertrophic cardiomyopathy due to incorrectly classified variants, according to a new study published today in the New England Journal of Medicine. The study could also have implications for other genetic diseases, and highlights the need for diversity in genetic studies.

Researchers from Harvard Medical School used publicly accessible exome sequencing data to identify variants that had previously been classified as causal for hypertrophic cardiomyopathy, but are overrepresented in the population.

The researchers initially mined sequence data from the National Heart, Lung, and Blood's Exome Sequencing project, reviewing variants considered pathogenic or disease-causing for hypertrophic cardiomyopathy, discovering many more variants in the general population that would be expected given the prevalence of the disease. This finding suggested either that penetrance was lower than expected, or that some of the variants were mislabeled. Looking more deeply into the data, the team found that five variants accounted for the majority of the misclassification and that those five variants were more common among African Americans.

Next, the team looked at records of patients who received genetic testing for hypertrophic cardiomyopathy at Partners HealthCare's Laboratory for Molecular Medicine and found 13 patients who had been misdiagnosed.

The researchers looked back through the medical literature to piece together the process by which the benign variants had originally been classified as pathogenic. They found that the initial studies on two variants — in the MYBPC3 and TNNI3 genes — included control samples near or below the minimum of the "accepted standard needed to corroborate pathogenicity," and that "none of the studies implicating these variants involved persons of African ancestry explicitly." Because the variants are rarer in individuals of European ancestry, they were falsely classified as pathogenic.

For the 13 patients who received misdiagnoses, the researchers wrote that it was unclear whether the families affected were re-contacted. Such misdiagnoses can lead to a number of problems, the authors wrote, including unnecessary stress, economic burdens, and increased screening. In addition, for patients who may show some clinical signs of hypertrophic cardiomyopathy but do not have a definitive diagnosis, a misclassification "may lead to the overestimation of the benefits of implantation of a cardioverter-defibrillator to prevent sudden cardiac death."

Going forward, the researchers suggest that more attention be paid to the diversity of participants in genetic studies and said that sequencing data from diverse individuals could be used both to evaluate novel variants as well as to reevaluate known variants. In addition, the authors said that a de-identified public database of genetic testing results could help resolve misclassifications and prevent future ones, and noted the need for "agile clinical systems" to make updated information "available in near-real time to physicians and genetic-testing laboratories."

These findings show that "a synergy of clinical, genetic, statistical, and political perspectives is needed to ensure that genomic medicine benefits all populations equally," they wrote.