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.
N1 - Publisher Copyright:
© 2022
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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U2 - 10.1016/j.gim.2022.07.007
DO - 10.1016/j.gim.2022.07.007
M3 - Article
C2 - 35943490
AN - SCOPUS:85136616122
SN - 1098-3600
VL - 24
SP - 2123
EP - 2133
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 10
ER -