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. 2022 Oct;24(10):2123-2133.
doi: 10.1016/j.gim.2022.07.007. Epub 2022 Aug 10.

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

Alborz Sherafati  1 , Omar Elsekaily  1 , Seyedmohammad Saadatagah  1 , David C Kochan  1 , Christopher Lee  1 , Georgia L Wiesner  2 , Cong Liu  3 , Lisa Dellefave-Castillo  4 , Bahram Namjou  5 , Emma F Perez  6 , Zachary M Salvati  7 , John J Connolly  8 , Hakon Hakonarson  9 , Marc S Williams  7 , Gail P Jarvik  10 , Wendy K Chung  11 , Elizabeth M McNally  4 , Teri A Manolio  12 , Iftikhar J Kullo  13
Affiliations

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

Alborz Sherafati et al. Genet Med. 2022 Oct.

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.

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Conflict of interest statement

Conflict of Interest The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Overview of participants included in penetrance and outcome analyses.
In phase III of eMERGE, 24,520 participants underwent targeted sequencing of 68 actionable genes, including 9 arteriopathy-associated genes (FBN1, SMAD3, TGFBR1, TGFBR2, ACTA2, SMAD4, MYH11, MYLK, and COL3A1). Electronic health records were reviewed for participants with a pathogenic/likely pathogenic variant to assess the presence of relevant clinical traits and penetrance estimation. Outcome analysis was performed for participants with returned results if they were aged >18 years and had no previous genetic testing before this study. *Geisinger participants were excluded from estimation of prevalence but were included in penetrance and outcomes analyses. eMERGE, Electronic Medical Records and Genomics.
See this image and copyright information in PMC

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