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N Engl J Med. 2016 Aug 18;375(7):655-65. doi: 10.1056/NEJMsa1507092.

Genetic Misdiagnoses and the Potential for Health Disparities.

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From the Departments of Biomedical Informatics (A.K.M., D.M.M., I.S.K.), Pathology (B.H.F.), and Medicine (B.A.M., J.L.), Harvard Medical School, the Departments of Pathology, Massachusetts General Hospital (B.H.F.), and the Department of Pathology (H.L.R.), Division of Cardiovascular Medicine (B.A.M.), and Department of Medicine (B.A.M., J.L.), Brigham and Women's Hospital, Boston, and the Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology (MIT) (A.K.M., I.S.K.), the Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine (B.H.F., H.L.R.), and the Computer Science and Artificial Intelligence Laboratory, MIT (P.S.), Cambridge - all in Massachusetts; and the Laboratory of Molecular Cardiology, Department of Cardiology, the Heart Center, University Hospital of Copenhagen, Rigshospitalet, and the Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen (M.S.O.) - both in Copenhagen.



For more than a decade, risk stratification for hypertrophic cardiomyopathy has been enhanced by targeted genetic testing. Using sequencing results, clinicians routinely assess the risk of hypertrophic cardiomyopathy in a patient's relatives and diagnose the condition in patients who have ambiguous clinical presentations. However, the benefits of genetic testing come with the risk that variants may be misclassified.


Using publicly accessible exome data, we identified variants that have previously been considered causal in hypertrophic cardiomyopathy and that are overrepresented in the general population. We studied these variants in diverse populations and reevaluated their initial ascertainments in the medical literature. We reviewed patient records at a leading genetic-testing laboratory for occurrences of these variants during the near-decade-long history of the laboratory.


Multiple patients, all of whom were of African or unspecified ancestry, received positive reports, with variants misclassified as pathogenic on the basis of the understanding at the time of testing. Subsequently, all reported variants were recategorized as benign. The mutations that were most common in the general population were significantly more common among black Americans than among white Americans (P<0.001). Simulations showed that the inclusion of even small numbers of black Americans in control cohorts probably would have prevented these misclassifications. We identified methodologic shortcomings that contributed to these errors in the medical literature.


The misclassification of benign variants as pathogenic that we found in our study shows the need for sequencing the genomes of diverse populations, both in asymptomatic controls and the tested patient population. These results expand on current guidelines, which recommend the use of ancestry-matched controls to interpret variants. As additional populations of different ancestry backgrounds are sequenced, we expect variant reclassifications to increase, particularly for ancestry groups that have historically been less well studied. (Funded by the National Institutes of Health.).

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