Research ArticleHuman Genetics

Aggregate penetrance of genomic variants for actionable disorders in European and African Americans

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Science Translational Medicine  09 Nov 2016:
Vol. 8, Issue 364, pp. 364ra151
DOI: 10.1126/scitranslmed.aag2367

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The problem of penetrance

It seems obvious that people who have mutations in genes known to cause disease in well-studied families would be more likely to also have the clinical features of disease if they were selected from the general population. But researchers have obtained mixed results on this point because of incomplete penetrance, i.e., not everyone who has a certain disease-causing mutation (a pathogenic variant) has the disease, raising questions about the value of genetic screening of people who are not sick. Natarajan and colleagues bring some clarity to this issue by examining two large groups of subjects—from the Framingham Heart Study and the African-American Jackson Heart Study—for the presence of mutations in 56 disease-related genes and for clinical features of their corresponding diseases. Even though the authors examined the genetic results of almost 5000 people, the number of these mutations was small. Nevertheless, these data clearly show that carrying a pathogenic variant markedly increases the chances of having the related disease.


In populations that have not been selected for family history of disease, it is unclear how commonly pathogenic variants (PVs) in disease-associated genes for rare Mendelian conditions are found and how often they are associated with clinical features of these conditions. We conducted independent, prospective analyses of participants in two community-based epidemiological studies to test the hypothesis that persons carrying PVs in any of 56 genes that lead to 24 dominantly inherited, actionable conditions are more likely to exhibit the clinical features of the corresponding diseases than those without PVs. Among 462 European American Framingham Heart Study (FHS) and 3223 African-American Jackson Heart Study (JHS) participants who were exome-sequenced, we identified and classified 642 and 4429 unique variants, respectively, in these 56 genes while blinded to clinical data. In the same participants, we ascertained related clinical features from the participants’ clinical history of cancer and most recent echocardiograms, electrocardiograms, and lipid measurements, without knowledge of variant classification. PVs were found in 5 FHS (1.1%) and 31 JHS (1.0%) participants. Carriers of PVs were more likely than expected, on the basis of incidence in noncarriers, to have related clinical features in both FHS (80.0% versus 12.4%) and JHS (26.9% versus 5.4%), yielding standardized incidence ratios of 6.4 [95% confidence interval (CI), 1.7 to 16.5; P = 7 × 10−4) in FHS and 4.7 (95% CI, 1.9 to 9.7; P = 3 × 10−4) in JHS. Individuals unselected for family history who carry PVs in 56 genes for actionable conditions have an increased aggregated risk of developing clinical features associated with the corresponding diseases.

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