Pathogenic variants in arteriopathy genes detected in a targeted sequencing study: Penetrance and 1-year outcomes after return of results

Alborz Sherafati; Omar Elsekaily; Seyedmohammad Saadatagah; David C. Kochan; Christopher Lee; Georgia L. Wiesner; Cong Liu; Lisa Dellefave-Castillo; Bahram Namjou; Emma F. Perez; Zachary M. Salvati; John J. Connolly; Hakon Hakonarson; Marc S. Williams; Gail P. Jarvik; Wendy K. Chung; Elizabeth M. McNally; Teri A. Manolio; Iftikhar J. Kullo

doi:10.1016/j.gim.2022.07.007

Pathogenic variants in arteriopathy genes detected in a targeted sequencing study: Penetrance and 1-year outcomes after return of results

Alborz Sherafati, Omar Elsekaily, Seyedmohammad Saadatagah, David C. Kochan, Christopher Lee, Georgia L. Wiesner, Cong Liu, Lisa Dellefave-Castillo, Bahram Namjou, Emma F. Perez, Zachary M. Salvati, John J. Connolly, Hakon Hakonarson, Marc S. Williams, Gail P. Jarvik, Wendy K. Chung, Elizabeth M. McNally, Teri A. Manolio, Iftikhar J. Kullo^*

^*Corresponding author for this work

Medicine, Cardiology Division

Research output: Contribution to journal › Article › peer-review

Abstract

Purpose: We estimated the penetrance of pathogenic/likely pathogenic (P/LP) variants in arteriopathy-related genes and assessed near-term outcomes following return of results. Methods: Participants (N = 24,520) in phase III of the Electronic Medical Records and Genomics network underwent targeted sequencing of 68 actionable genes, including 9 genes associated with arterial aneurysmal diseases. Penetrance was estimated on the basis of the presence of relevant clinical traits. Outcomes occurring within 1 year of return of results included new diagnoses, referral to a specialist, new tests ordered, surveillance initiated, and new medications started. Results: P/LP variants were present in 34 participants. The average penetrance across genes was 59%, ranging from 86% for FBN1 variants to 25% for SMAD3. Of 16 participants in whom results were returned, 1-year outcomes occurred in 63%. A new diagnosis was made in 44% of the participants, 56% were referred to a specialist, a new test was ordered in 44%, surveillance was initiated in 31%, and a new medication was started in 31%. Conclusion: Penetrance of P/LP variants in arteriopathy-related genes, identified in a large, targeted sequencing study, was variable and overall lower than that reported in clinical cohorts. Meaningful outcomes within the first year were noted in 63% of participants who received results.

Original language	English (US)
Pages (from-to)	2123-2133
Number of pages	11
Journal	Genetics in Medicine
Volume	24
Issue number	10
DOIs	https://doi.org/10.1016/j.gim.2022.07.007
State	Published - Oct 2022

Funding

The Electronic Medical Records and Genomics phase III network was initiated and funded by the National Human Genome Research Institute through the following grants: U01HG008657 (Kaiser Permanente Washington Health Research Institute/University of Washington), U01HG008685 (Brigham and Women's Hospital), U01HG008672 (Vanderbilt University Medical Center), U01HG008666 (Cincinnati Children's Hospital Medical Center), U01HG006379 (Mayo Clinic), U01HG008679 (Geisinger Clinic), U01HG008680 (Columbia University Health Sciences), U01HG008684 (Children's Hospital of Philadelphia), U01HG008673 (Northwestern University), MD007593 (Meharry Medical College), U01HG008701 (Vanderbilt University Medical Center serving as the Coordinating Center), U01HG008676 (Partners Healthcare/Broad Institute), and U01HG008664 (Baylor College of Medicine). IJK was additionally funded by K24 HL137010. EMM consults for Amgen, Avidity, AstraZeneca, 4D Molecular Therapeutics, Cytokinetics, Invitae, Janssen, PepGen, Pfizer, and Tenaya and is a founder of Ikaika Therapeutics, all unrelated to the content of this manuscript. Conceptualization: I.J.K. G.L.W. C.L. L.DC. B.N. M.S.W. G.P.J. W.K.C. E.M.M. T.A.M. H.H.; Data Curation: D.C.K. O.E. Ch.L. A.S. E.F.P. Z.M.S. J.J.C. B.N.; Formal Analysis: A.S. O.E. S.S.; Funding Acquisition: I.J.K.; Investigation: O.E. A.S. S.S. D.C.K. Ch.L.; Methodology: I.J.K. G.L.W. C.L. L.DC. B.N. M.S.W. G.P.J. W.K.C. E.M.M. T.A.M. H.H.; Resources: I.J.K.; Supervision: I.J.K.; Visualization: A.S. O.E.; Writing-original draft: I.J.K. A.S. O.E.; Writing-review and editing: I.J.K. G.L.W. C.L. L.D. M.S.W. G.P.J. W.K.C. E.M.M. T.A.M. D.C.K. S.S. A.S. E.F.P. Z.M.S. J.J.C. H.H. Participants were asked to complete a study consent form and health questionnaires and provide a blood sample (if an existing sample was not available) to participate in this study. This study and the informed consent process were approved by the Mayo Institutional Review Board (as the main Institutional Review Board of the first and corresponding authors’ institutions) as well as other Institutional Review Boards at the Electronic Medical Records and Genomics sites. More information about the ethical considerations in Electronic Medical Records and Genomics phase III study, including the Mayo Clinic Biobank, are provided at https://pubmed.ncbi.nlm.nih.gov/29301385/. Information about the Mayo Clinic Biobank's collection and enrollment methods are provided at https://pubmed.ncbi.nlm.nih.gov/24001487/. The link to the Mayo Clinic Biobank website is as follows: https://www.mayo.edu/research/centers-programs/mayo-clinic-biobank/overview. The Electronic Medical Records and Genomics phase III network was initiated and funded by the National Human Genome Research Institute through the following grants: U01HG008657 (Kaiser Permanente Washington Health Research Institute/University of Washington), U01HG008685 (Brigham and Women’s Hospital), U01HG008672 (Vanderbilt University Medical Center), U01HG008666 (Cincinnati Children’s Hospital Medical Center), U01HG006379 (Mayo Clinic), U01HG008679 (Geisinger Clinic), U01HG008680 (Columbia University Health Sciences), U01HG008684 (Children’s Hospital of Philadelphia), U01HG008673 (Northwestern University), MD007593 (Meharry Medical College), U01HG008701 (Vanderbilt University Medical Center serving as the Coordinating Center), U01HG008676 (Partners Healthcare/Broad Institute), and U01HG008664 (Baylor College of Medicine). IJK was additionally funded by K24 HL137010. EMM consults for Amgen, Avidity, AstraZeneca, 4D Molecular Therapeutics, Cytokinetics, Invitae, Janssen, PepGen, Pfizer, and Tenaya and is a founder of Ikaika Therapeutics, all unrelated to the content of this manuscript.

Keywords

Aortic aneurysm
Aortic dissection
Arteriopathy
Genetic screening
Marfan syndrome

ASJC Scopus subject areas

Genetics(clinical)

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10.1016/j.gim.2022.07.007

Cite this

Sherafati, A., Elsekaily, O., Saadatagah, S., Kochan, D. C., Lee, C., Wiesner, G. L., Liu, C., Dellefave-Castillo, L., Namjou, B., Perez, E. F., Salvati, Z. M., Connolly, J. J., Hakonarson, H., Williams, M. S., Jarvik, G. P., Chung, W. K., McNally, E. M., Manolio, T. A., & Kullo, I. J. (2022). Pathogenic variants in arteriopathy genes detected in a targeted sequencing study: Penetrance and 1-year outcomes after return of results. Genetics in Medicine, 24(10), 2123-2133. https://doi.org/10.1016/j.gim.2022.07.007

@article{06671beeb25747d3916c3d3edc2b82d8,

title = "Pathogenic variants in arteriopathy genes detected in a targeted sequencing study: Penetrance and 1-year outcomes after return of results",

abstract = "Purpose: We estimated the penetrance of pathogenic/likely pathogenic (P/LP) variants in arteriopathy-related genes and assessed near-term outcomes following return of results. Methods: Participants (N = 24,520) in phase III of the Electronic Medical Records and Genomics network underwent targeted sequencing of 68 actionable genes, including 9 genes associated with arterial aneurysmal diseases. Penetrance was estimated on the basis of the presence of relevant clinical traits. Outcomes occurring within 1 year of return of results included new diagnoses, referral to a specialist, new tests ordered, surveillance initiated, and new medications started. Results: P/LP variants were present in 34 participants. The average penetrance across genes was 59%, ranging from 86% for FBN1 variants to 25% for SMAD3. Of 16 participants in whom results were returned, 1-year outcomes occurred in 63%. A new diagnosis was made in 44% of the participants, 56% were referred to a specialist, a new test was ordered in 44%, surveillance was initiated in 31%, and a new medication was started in 31%. Conclusion: Penetrance of P/LP variants in arteriopathy-related genes, identified in a large, targeted sequencing study, was variable and overall lower than that reported in clinical cohorts. Meaningful outcomes within the first year were noted in 63% of participants who received results.",

keywords = "Aortic aneurysm, Aortic dissection, Arteriopathy, Genetic screening, Marfan syndrome",

author = "Alborz Sherafati and Omar Elsekaily and Seyedmohammad Saadatagah and Kochan, {David C.} and Christopher Lee and Wiesner, {Georgia L.} and Cong Liu and Lisa Dellefave-Castillo and Bahram Namjou and Perez, {Emma F.} and Salvati, {Zachary M.} and Connolly, {John J.} and Hakon Hakonarson and Williams, {Marc S.} and Jarvik, {Gail P.} and Chung, {Wendy K.} and McNally, {Elizabeth M.} and Manolio, {Teri A.} and Kullo, {Iftikhar J.}",

note = "Publisher Copyright: {\textcopyright} 2022",

year = "2022",

month = oct,

doi = "10.1016/j.gim.2022.07.007",

language = "English (US)",

volume = "24",

pages = "2123--2133",

journal = "Genetics in Medicine",

issn = "1098-3600",

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Sherafati, A, Elsekaily, O, Saadatagah, S, Kochan, DC, Lee, C, Wiesner, GL, Liu, C, Dellefave-Castillo, L, Namjou, B, Perez, EF, Salvati, ZM, Connolly, JJ, Hakonarson, H, Williams, MS, Jarvik, GP, Chung, WK, McNally, EM, Manolio, TA & Kullo, IJ 2022, 'Pathogenic variants in arteriopathy genes detected in a targeted sequencing study: Penetrance and 1-year outcomes after return of results', Genetics in Medicine, vol. 24, no. 10, pp. 2123-2133. https://doi.org/10.1016/j.gim.2022.07.007

TY - JOUR

T1 - Pathogenic variants in arteriopathy genes detected in a targeted sequencing study

T2 - Penetrance and 1-year outcomes after return of results

AU - Sherafati, Alborz

AU - Elsekaily, Omar

AU - Saadatagah, Seyedmohammad

AU - Kochan, David C.

AU - Lee, Christopher

AU - Wiesner, Georgia L.

AU - Liu, Cong

AU - Dellefave-Castillo, Lisa

AU - Namjou, Bahram

AU - Perez, Emma F.

AU - Salvati, Zachary M.

AU - Connolly, John J.

AU - Hakonarson, Hakon

AU - Williams, Marc S.

AU - Jarvik, Gail P.

AU - Chung, Wendy K.

AU - McNally, Elizabeth M.

AU - Manolio, Teri A.

AU - Kullo, Iftikhar J.

PY - 2022/10

Y1 - 2022/10

N2 - Purpose: We estimated the penetrance of pathogenic/likely pathogenic (P/LP) variants in arteriopathy-related genes and assessed near-term outcomes following return of results. Methods: Participants (N = 24,520) in phase III of the Electronic Medical Records and Genomics network underwent targeted sequencing of 68 actionable genes, including 9 genes associated with arterial aneurysmal diseases. Penetrance was estimated on the basis of the presence of relevant clinical traits. Outcomes occurring within 1 year of return of results included new diagnoses, referral to a specialist, new tests ordered, surveillance initiated, and new medications started. Results: P/LP variants were present in 34 participants. The average penetrance across genes was 59%, ranging from 86% for FBN1 variants to 25% for SMAD3. Of 16 participants in whom results were returned, 1-year outcomes occurred in 63%. A new diagnosis was made in 44% of the participants, 56% were referred to a specialist, a new test was ordered in 44%, surveillance was initiated in 31%, and a new medication was started in 31%. Conclusion: Penetrance of P/LP variants in arteriopathy-related genes, identified in a large, targeted sequencing study, was variable and overall lower than that reported in clinical cohorts. Meaningful outcomes within the first year were noted in 63% of participants who received results.

AB - Purpose: We estimated the penetrance of pathogenic/likely pathogenic (P/LP) variants in arteriopathy-related genes and assessed near-term outcomes following return of results. Methods: Participants (N = 24,520) in phase III of the Electronic Medical Records and Genomics network underwent targeted sequencing of 68 actionable genes, including 9 genes associated with arterial aneurysmal diseases. Penetrance was estimated on the basis of the presence of relevant clinical traits. Outcomes occurring within 1 year of return of results included new diagnoses, referral to a specialist, new tests ordered, surveillance initiated, and new medications started. Results: P/LP variants were present in 34 participants. The average penetrance across genes was 59%, ranging from 86% for FBN1 variants to 25% for SMAD3. Of 16 participants in whom results were returned, 1-year outcomes occurred in 63%. A new diagnosis was made in 44% of the participants, 56% were referred to a specialist, a new test was ordered in 44%, surveillance was initiated in 31%, and a new medication was started in 31%. Conclusion: Penetrance of P/LP variants in arteriopathy-related genes, identified in a large, targeted sequencing study, was variable and overall lower than that reported in clinical cohorts. Meaningful outcomes within the first year were noted in 63% of participants who received results.

KW - Aortic aneurysm

KW - Aortic dissection

KW - Arteriopathy

KW - Genetic screening

KW - Marfan syndrome

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DO - 10.1016/j.gim.2022.07.007

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SN - 1098-3600

VL - 24

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EP - 2133

JO - Genetics in Medicine

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ER -

Pathogenic variants in arteriopathy genes detected in a targeted sequencing study: Penetrance and 1-year outcomes after return of results

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