Iftikhar J Kullo, Carol R Horowitz, Lisa Bastarache, Benjamin Berkman, Leslie Biesecker, Kyle Brothers, April P Carson, Keith Diaz, Richard A Gibbs, Robert C Green, Heather Hampel, Candace Henley, Jodell E Linder, Gail P Jarvik, Sadiya S Khan, Barry Make, Samuli Ripatti, Mimsie Robinson, Juliann M Savatt, Gabriel Q Shaibi, Stephen Olufemi Sodeke, Colin Wise, Yuling Hong, Ye Yan, Ronit I Yarden
The return of secondary genomic findings (ROSF) to participants in observational cohort studies has evolved from a topic of debate to an accepted standard. This Perspective synthesizes the proceedings of a 2024 National Heart, Lung and Blood Institute-sponsored workshop and the broader literature to provide updated guidance for ROSF. Building on the 2010 National Heart, Lung and Blood Institute Working Group recommendations and the 2014 Clinical Sequencing Exploratory Research/Electronic Medical Records and Genomics 'floor and ceiling' framework, we address four areas: an integrated ethical framework for observational cohort settings; the emerging challenge of returning novel result types beyond monogenic variants, including polygenic risk scores, somatic mosaicism and pharmacogenomic findings; health equity and community engagement as structural prerequisites for ethical ROSF; and scalability challenges, including technology-assisted disclosure. Drawing on implementation experience from large-scale sequencing programs, we offer recommendations that balance researcher obligations with participant autonomy and equitable access to the benefits of genomic research.