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Genetic tests may be misdiagnosing hypertrophic cardiomyopathy in black Americans
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Benign variants are disproportionately misclassified as pathogenic in genetic testing for hypertrophic cardiomyopathy in black Americans because of lack of diversity in genome sequencing, according to a study published in The New England Journal of Medicine.
“We believe that what we’re seeing in the case of hypertrophic cardiomyopathy may be the tip of the iceberg of a larger problem that transcends a single genetic disease,” Arjun Manrai, PhD, a research fellow in the department of biomedical informatics at Harvard Medical School, said in a press release. “We hope our study motivates a systematic review of this issue across other genetic conditions.”
Manrai and colleagues discovered through their analysis of more than 8,000 DNA samples from the NIH’s Mendelian Exome Sequencing Project, the 1,000 Genomes Project and the Human Genome Diversity Project that the false-positive diagnoses are the result of clinical studies in which the majority of the control groups consisted of white participants who tend to have fewer benign variants than black participants.
Benign variants
Between 2.9% and 27% of black Americans have one or more of the five high-frequency benign genetic variants associated with hypertrophic cardiomyopathy compared with the 0.02% to 2.9% of white Americans (P < .001), according to the researchers.
In addition, after examining the health records of more than 2,000 patients and their family members at the Laboratory for Molecular Medicine, Partners Healthcare, Boston, between 2004 and 2014, the researchers observed that seven patients who received notification that they had a pathogenic mutation (TNN13 P82S or MYBPC3 G278E) were reclassified as benign. Of those seven patients, five were black and two were of unknown ancestry. The need for more reclassification is expected in the next decade, according to the researchers.
Manrai and colleagues also found that the five original genetic studies on hypertrophic cardiomyopathy did not include black participants in the control groups.
“Our study powerfully illustrates the importance of racial and ethnic diversity in research,” Isaac S. Kohane, MD, PhD, chair of the department of biomedical informatics, Harvard Medical School, said in the release. “Racial and ethnical inclusiveness improves the validity and accuracy of clinical trials and, in doing so, can better guide clinical decision making and choice of optimal therapy. This is the essence of precision medicine.”
‘Moral imperative’
The researchers also illustrated using statistical simulations that even small studies can be racially diverse. They gave an example of a sample of 200 people that included 20 black participants. This sample would only have a 50% chance of a correct diagnosis, but if one-third of the population or half the population were black, then accuracy would improve to 80% and 90%, respectively, Manrai and colleagues wrote.
“Ensuring that genomic medicine benefits all people and all populations equally is nothing short of a moral imperative, not only for scientists and clinicians but for political and health policy powers that be,” Kohane said in the release. – by Tracey Romero
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Robert Roberts, MD, MACC, FRSC, FRCPC, LLD (Hon.)
Studies in which DNA mutations are being sought as a cause for a disease such as familial hypertrophic cardiomyopathy are vulnerable with respect to African Americans. The DNA of Africans and African Americans has been modified much more than the other races since they stayed in Africa. The DNA of all other races are derived from individuals that left Africa about 100,000 years ago. The sequencing of the human genome, which until recently was Caucasians and not Africans, has been used as the standard for comparison of potential disease-causing mutations.
It is well-recognized that mutations that are disease-producing in groups such as Caucasians or Asians or Chinese may not necessarily be disease-causing in Africans or African Americans. One good example is the recent discovery of 9p21, a genetic risk variant for CAD, which is not a risk factor in Africans or African Americans but is a risk factor for all the others who left Africa 100,000 years ago. Another example is that Africans have a mutation that bestows resistance to malaria, and when they come to cooler climates, the same mutation induces sickle cell anemia. Other races, including Caucasians, have lost that mutation. Thus, if one is identifying a disease-causing mutation solely on the basis of a DNA sequence, it may become necessary to compare the DNA sequence of an African or African American to an African or African-American reference sequence.
In the past, we would have determined if hypertrophic cardiomyopathy is due to a mutation by doing linkage analysis, which requires 7 to 10 affected individuals from at least two generations. In linkage analysis, we can show by segregation that the mutation is indeed causal of the disease. However, since it is often impossible to have two-generation families with an adequate number of individuals affected with hypertrophic cardiomyopathy, we frequently today turn to sequencing. In the case of the Africans or African Americans, this has further problems, for the reasons I stated earlier.
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