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

Christopher Lee, Omar Elsekaily, David C. Kochan, Lubna Alhalabi, Faizan Faizee, Richard Sharp, Noralane M. Lindor, Iftikhar J. Kullo

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1192-1201
Number of pages10
JournalGenetics in Medicine
Issue number7
StatePublished - Jul 2021

ASJC Scopus subject areas

  • Genetics(clinical)


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