Genetic Misdiagnoses and the Potential for Health Disparities
Top Cited Papers
- 18 August 2016
- journal article
- research article
- Published by Massachusetts Medical Society in The New England Journal of Medicine
- Vol. 375 (7), 655-665
- https://doi.org/10.1056/nejmsa1507092
Abstract
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.)Keywords
This publication has 38 references indexed in Scilit:
- ClinVar: public archive of relationships among sequence variation and human phenotypeNucleic Acids Research, 2013
- An integrated map of genetic variation from 1,092 human genomesNature, 2012
- Burden of Rare Sarcomere Gene Variants in the Framingham and Jackson Heart Study CohortsAmerican Journal of Human Genetics, 2012
- A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding GenesScience, 2012
- Long-Term Effects of Enzyme Replacement Therapy on Fabry CardiomyopathyCirculation, 2009
- The Human Gene Mutation Database: 2008 updateGenome Medicine, 2009
- Shared Genetic Causes of Cardiac Hypertrophy in Children and AdultsThe New England Journal of Medicine, 2008
- Sarcomere Protein Gene Mutations in Hypertrophic Cardiomyopathy of the ElderlyCirculation, 2002
- Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USAThe Lancet, 2002
- The Risk of Cancer Associated with Specific Mutations ofBRCA1andBRCA2among Ashkenazi JewsThe New England Journal of Medicine, 1997