Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jul;23(7):1192-1201.
doi: 10.1038/s41436-021-01142-9. Epub 2021 Apr 6.

Penetrance and outcomes at 1-year following return of actionable variants identified by genome sequencing

Christopher Lee #  1 , Omar Elsekaily #  1 , David C Kochan  1 , Lubna Alhalabi  1 , Faizan Faizee  1 , Richard Sharp  2 , Noralane M Lindor  3 , Iftikhar J Kullo  4
Affiliations

Penetrance and outcomes at 1-year following return of actionable variants identified by genome sequencing

Christopher Lee et al. Genet Med. 2021 Jul.

Abstract

Purpose: We estimated penetrance of actionable genetic variants and assessed near-term outcomes following return of results (RoR).

Methods: Participants (n = 2,535) with hypercholesterolemia and/or colon polyps underwent targeted sequencing of 68 genes and 14 single-nucleotide variants. Penetrance was estimated based on presence of relevant traits in the electronic health record (EHR). Outcomes occurring within 1-year of RoR were ascertained by EHR review. Analyses were stratified by tier 1 and non-tier 1 disorders.

Results: Actionable findings were present in 122 individuals and results were disclosed to 98. The average penetrance for tier 1 disorder variants (67%; n = 58 individuals) was higher than in non-tier 1 variants (46.5%; n = 58 individuals). After excluding 45 individuals (decedents, nonresponders, known genetic diagnoses, mosaicism), ≥1 outcomes were noted in 83% of 77 participants following RoR; 78% had a process outcome (referral to a specialist, new testing, surveillance initiated); 68% had an intermediate outcome (new test finding or diagnosis); 19% had a clinical outcome (therapy modified, risk reduction surgery). Risk reduction surgery occurred more often in participants with tier 1 than those with non-tier 1 variants.

Conclusion: Relevant phenotypic traits were observed in 57% whereas a clinical outcome occurred in 19% of participants with actionable genomic variants in the year following RoR.

PubMed Disclaimer

Conflict of interest statement

DISCLOSURE

The authors declare they have no disclosures regarding conflict of interest with respect to this manuscript.

Figures

Figure 1.
Figure 1.. Participant Selection for Penetrance and Outcomes Analyses.
*Two participants had 2 actionable variants each; total number of actionable variants identified = 123
See this image and copyright information in PMC

References

    1. Feero WG, Wicklund CA, Veenstra D. Precision medicine, genome sequencing, and improved population health. JAMA 2018;319:1979–80. - PubMed
    1. ACMG Board of Directors. The use of ACMG secondary findings recommendations for general population screening: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2019;21:1467–8. - PubMed
    1. Hosseini SM, Kim R, Udupa S, et al. Reappraisal of reported genes for sudden arrhythmic death: Evidence-based evaluation of gene validity for Brugada Syndrome. Circulation 2018;138:1195–205. - PMC - PubMed
    1. Natarajan P, Gold NB, Bick AG, et al. Aggregate penetrance of genomic variants for actionable disorders in European and African Americans. Sci Transl Med 2016;8:364ra151. - PMC - PubMed
    1. Shah N, Hou YC, Yu HC, et al. Identification of misclassified ClinVar variants via disease population prevalence. Am J Hum Genet 2018;102:609–19. - PMC - PubMed

Publication types

LinkOut - more resources