The Return of Actionable Variants Empirical (RAVE) Study, a Mayo Clinic Genomic Medicine Implementation Study: Design and Initial Results.

Kullo IJ1, Olson J2, Fan X3, Jose M3, Safarova M3, Radecki Breitkopf C2, Winkler E4, Kochan DC3, Snipes S3, Pacyna JE2, Carney M3, Chute CG5, Gupta J6, Jose S6, Venner E7, Murugan M7, Jiang Y7, Zordok M3, Farwati M3, Philogene M3, Smith E3, Shaibi GQ8, Caraballo P9, Freimuth R2, Lindor NM10, Sharp R2, Thibodeau SN11.

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Abstract

OBJECTIVES:

To identify clinically actionable genetic variants from targeted sequencing of 68 disease-related genes, estimate their penetrance, and assess the impact of disclosing results to participants and providers.

PATIENTS AND METHODS:

The Return of Actionable Variants Empirical (RAVE) Study investigates outcomes following the return of pathogenic/likely pathogenic (P/LP) variants in 68 disease-related genes. The study was initiated in December 2016 and is ongoing. Targeted sequencing was performed in 2533 individuals with hyperlipidemia or colon polyps. The electronic health records (EHRs) of participants carrying P/LP variants in 36 cardiovascular disease (CVD) genes were manually reviewed to ascertain the presence of relevant traits. Clinical outcomes, health care utilization, family communication, and ethical and psychosocial implications of disclosure of genomic results are being assessed by surveys, telephone interviews, and EHR review.

RESULTS:

Of 29,208 variants in the 68 genes, 1915 were rare (frequency <1%) and putatively functional, and 102 of these (60 in 36 CVD genes) were labeled P/LP based on the American College of Medical Genetics and Genomics framework. Manual review of the EHRs of participants (n=73 with P/LP variants in CVD genes) revealed that 33 had the expected trait(s); however, only 6 of 45 participants with non-familial hypercholesterolemia (FH) P/LP variants had the expected traits.

CONCLUSION:

Expected traits were present in 13% of participants with P/LP variants in non-FH CVD genes, suggesting low penetrance; this estimate may change with additional testing performed as part of the clinical evaluation. Ongoing analyses of the RAVE Study will inform best practices for genomic medicine.