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

Abstract

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.

Genetics and Insurance in Australia: Concerns around a Self-Regulated Industry

“…Genomic information risk predictions are not yet uniformly supported by representative and robust population data, especially data from individuals of non-European ethnicity [33] . Studies in healthy individuals are suggesting that genetic variations previously thought to be strongly indicative of disease development may not carry such a high risk or may even be benign [34][35][36][37][38][39] . Predicting disease risk based on genomic information is difficult, even for genomic experts.…”

15th International Symposium on IgANephropathy – IIgANN 2018, Buenos Aires, September 27-29, 2018: Summaries

“…Such pharmacogenomics studies are still nascent but will become routine as larger datasets become available. Finally, increasing use of genome-wide clinical sequencing may reveal incidental findings that are unrelated to the primary cause of disease but may nonetheless inform disease management and therapy [22,23]. For example, incidental identification of mutations predisposing to hereditary cancer are detected in 1-4% of the population and would influence the choice for immunosuppression for patient with IgAN.…”

“…These prediction models also have the potential to improve future research in IgAN. Several clinical trials in IgAN have failed their primary end-point assessments partly due to inadvertently recruiting low-risk patients whose disease did not progress [17][18][19][20][21][22]. An accurate risk prediction tool will allow recruitment of higher risk patients, thus increasing power and improving the feasibility and cost of clinical trials in IgAN [23].…”

Precision medicine driven by cancer systems biology

“…Not surprisingly, conservative models of privacy were challenged long before the advent of precision medicine by direct-to-consumer genetic tests and population genome research projects [28–31]. Instead of relying on generalizable knowledge, tomorrow’s repositories are moving towards fully consented models motivated by a main benefit of being able to associate longitudinal health records [32–34] (Fig. 1).…”