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

Research output: Contribution to journalArticlepeer-review


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 languageEnglish (US)
Pages (from-to)2123-2133
Number of pages11
JournalGenetics in Medicine
Issue number10
StatePublished - Oct 2022


  • Aortic aneurysm
  • Aortic dissection
  • Arteriopathy
  • Genetic screening
  • Marfan syndrome

ASJC Scopus subject areas

  • Genetics(clinical)


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