The Return of Actionable Variants Empirical (RAVE) Study, a Mayo Clinic Genomic Medicine Implementation Study

Design and Initial Results

Iftikhar Jan Kullo, Janet E Olson, Xiao Fan, Merin Jose, Maya Safarova, Carmen Radecki Breitkopf, Erin Winkler, David C. Kochan, Sara Snipes, Joel E. Pacyna, Meaghan Carney, Christopher G. Chute, Jyoti Gupta, Sheethal Jose, Eric Venner, Mullai Murugan, Yunyun Jiang, Magdi Zordok, Medhat Farwati, Maraisha Philogene & 7 others Erica Smith, Gabriel Q. Shaibi, Pedro Caraballo, Robert Freimuth, Noralane Morey Lindor, Richard R Sharp, Stephen N Thibodeau

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1600-1610
Number of pages11
JournalMayo Clinic Proceedings
Volume93
Issue number11
DOIs
StatePublished - Nov 1 2018

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Medicine
Electronic Health Records
Genes
Cardiovascular Diseases
Penetrance
Patient Acceptance of Health Care
Disclosure
Genomics
Polyps
Hypercholesterolemia
Hyperlipidemias
Practice Guidelines
Colon
Communication
Outcome Assessment (Health Care)
Interviews

ASJC Scopus subject areas

  • Medicine(all)

Cite this

The Return of Actionable Variants Empirical (RAVE) Study, a Mayo Clinic Genomic Medicine Implementation Study : Design and Initial Results. / Kullo, Iftikhar Jan; Olson, Janet E; Fan, Xiao; Jose, Merin; Safarova, Maya; Radecki Breitkopf, Carmen; Winkler, Erin; Kochan, David C.; Snipes, Sara; Pacyna, Joel E.; Carney, Meaghan; Chute, Christopher G.; Gupta, Jyoti; Jose, Sheethal; Venner, Eric; Murugan, Mullai; Jiang, Yunyun; Zordok, Magdi; Farwati, Medhat; Philogene, Maraisha; Smith, Erica; Shaibi, Gabriel Q.; Caraballo, Pedro; Freimuth, Robert; Lindor, Noralane Morey; Sharp, Richard R; Thibodeau, Stephen N.

In: Mayo Clinic Proceedings, Vol. 93, No. 11, 01.11.2018, p. 1600-1610.

Research output: Contribution to journalArticle

Kullo, IJ, Olson, JE, Fan, X, Jose, M, Safarova, M, Radecki Breitkopf, C, Winkler, E, Kochan, DC, Snipes, S, Pacyna, JE, Carney, M, Chute, CG, Gupta, J, Jose, S, Venner, E, Murugan, M, Jiang, Y, Zordok, M, Farwati, M, Philogene, M, Smith, E, Shaibi, GQ, Caraballo, P, Freimuth, R, Lindor, NM, Sharp, RR & Thibodeau, SN 2018, 'The Return of Actionable Variants Empirical (RAVE) Study, a Mayo Clinic Genomic Medicine Implementation Study: Design and Initial Results', Mayo Clinic Proceedings, vol. 93, no. 11, pp. 1600-1610. https://doi.org/10.1016/j.mayocp.2018.06.026
Kullo, Iftikhar Jan ; Olson, Janet E ; Fan, Xiao ; Jose, Merin ; Safarova, Maya ; Radecki Breitkopf, Carmen ; Winkler, Erin ; Kochan, David C. ; Snipes, Sara ; Pacyna, Joel E. ; Carney, Meaghan ; Chute, Christopher G. ; Gupta, Jyoti ; Jose, Sheethal ; Venner, Eric ; Murugan, Mullai ; Jiang, Yunyun ; Zordok, Magdi ; Farwati, Medhat ; Philogene, Maraisha ; Smith, Erica ; Shaibi, Gabriel Q. ; Caraballo, Pedro ; Freimuth, Robert ; Lindor, Noralane Morey ; Sharp, Richard R ; Thibodeau, Stephen N. / The Return of Actionable Variants Empirical (RAVE) Study, a Mayo Clinic Genomic Medicine Implementation Study : Design and Initial Results. In: Mayo Clinic Proceedings. 2018 ; Vol. 93, No. 11. pp. 1600-1610.
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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.",
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T1 - The Return of Actionable Variants Empirical (RAVE) Study, a Mayo Clinic Genomic Medicine Implementation Study

T2 - Design and Initial Results

AU - Kullo, Iftikhar Jan

AU - Olson, Janet E

AU - Fan, Xiao

AU - Jose, Merin

AU - Safarova, Maya

AU - Radecki Breitkopf, Carmen

AU - Winkler, Erin

AU - Kochan, David C.

AU - Snipes, Sara

AU - Pacyna, Joel E.

AU - Carney, Meaghan

AU - Chute, Christopher G.

AU - Gupta, Jyoti

AU - Jose, Sheethal

AU - Venner, Eric

AU - Murugan, Mullai

AU - Jiang, Yunyun

AU - Zordok, Magdi

AU - Farwati, Medhat

AU - Philogene, Maraisha

AU - Smith, Erica

AU - Shaibi, Gabriel Q.

AU - Caraballo, Pedro

AU - Freimuth, Robert

AU - Lindor, Noralane Morey

AU - Sharp, Richard R

AU - Thibodeau, Stephen N

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

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