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
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
ACMG Member Login
Are you an ACMG Member? Sign in for online access.Subscribe:
Subscribe to Genetics in MedicineAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015; 17: 405-424https://doi.org/10.1038/gim.2015.30
- Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2021 update: a policy statement of the American College of Medical Genetics and Genomics (ACMG).Genet Med. 2021; 23: 1391-1398https://doi.org/10.1038/s41436-021-01171-4
Kalia SS, Adelman K, Bale SJ et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017;19(2):249-255. Published corrections appears in Genet Med. 2017;19(4):484. https://doi.org/10.1038/gim.2016.190.
Miller DT, Lee K, Chung WK et al. ACMG SF v3. 0 List for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(8):1381-1390. Published correction appears in Genet Med. 2021;23(8):1582-1584. https://doi.org/10.1038/s41436-021-01172-3.
- Genes associated with thoracic aortic aneurysm and dissection: 2019 update and clinical implications.Aorta (Stamford). 2019; 7: 99-107https://doi.org/10.1055/s-0039-3400233
- The genetics of aortopathies: hereditary thoracic aortic aneurysms and dissections.Am J Med Genet C Semin Med Genet. 2020; 184: 136-148https://doi.org/10.1002/ajmg.c.31771
- Genetics and precision medicine: heritable thoracic aortic disease.Med Clin North Am. 2019; 103: 1005-1019https://doi.org/10.1016/j.mcna.2019.08.001
- Penetrance and outcomes at 1-year following return of actionable variants identified by genome sequencing.Genet Med. 2021; 23: 1192-1201https://doi.org/10.1038/s41436-021-01142-9
- The electronic medical records and genomics (eMERGE) network: past, present, and future.Genet Med. 2013; 15: 761-771https://doi.org/10.1038/gim.2013.72
- The eMERGE Network: a consortium of biorepositories linked to electronic medical records data for conducting genomic studies.BMC Med Genomics. 2011; 4: 13https://doi.org/10.1186/1755-8794-4-13
- The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.Bull World Health Organ. 2007; 85: 867-872https://doi.org/10.2471/BLT.07.045120
- Frequency of genomic incidental findings among 21,915 eMERGE network participants.Genet Med. 2020; 22: 1470-1477https://doi.org/10.1038/s41436-020-0810-9
- Electronic address: [email protected], eMERGE Consortium. Harmonizing clinical sequencing and interpretation for the eMERGE III network.Am J Hum Genet. 2019; 105: 588-605https://doi.org/10.1016/j.ajhg.2019.07.018
- Ethical considerations related to return of results from genomic medicine projects: the eMERGE network (phase III) experience.J Pers Med. 2018; 8: 2https://doi.org/10.3390/jpm8010002
- Returning results in the genomic era: initial experiences of the eMERGE Network.J Pers Med. 2020; 10: 30https://doi.org/10.3390/jpm10020030
Green RC, Berg JS, Grody WW et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15(7):565-574. Published correction appears in Genet Med. 2017;19(5):606. https://doi.org/10.1038/gim.2013.73.
- The Return of Actionable Variants Empirical (RAVE) Study, a Mayo Clinic genomic medicine implementation study: design and initial results.Mayo Clin Proc. 2018; 93: 1600-1610https://doi.org/10.1016/j.mayocp.2018.06.026
- Research Electronic Data Capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support.J Biomed Inform. 2009; 42: 377-381https://doi.org/10.1016/j.jbi.2008.08.010
- Normal limits in relation to age, body size and gender of two-dimensional echocardiographic aortic root dimensions in persons≥ 15 years of age.Am J Cardiol. 2012; 110: 1189-1194https://doi.org/10.1016/j.amjcard.2012.05.063
- Early lessons from the implementation of genomic medicine programs.Annu Rev Genomics Hum Genet. 2019; 20: 389-411https://doi.org/10.1146/annurev-genom-083118-014924
- Building evidence and measuring clinical outcomes for genomic medicine.Lancet. 2019; 394: 604-610https://doi.org/10.1016/S0140-6736(19)31278-4
- A genotype-first approach to exploring Mendelian cardiovascular traits with clear external manifestations.Genet Med. 2021; 23: 94-102https://doi.org/10.1038/s41436-020-00973-2
- The genetics of thoracic aortic aneurysms and dissection: a clinical perspective.Biomolecules. 2020; 10: 182https://doi.org/10.3390/biom10020182
- 1 in 38 individuals at risk of a dominant medically actionable disease.Eur J Hum Genet. 2019; 27: 325-330https://doi.org/10.1038/s41431-018-0284-2
- Aggregate penetrance of genomic variants for actionable disorders in European and African Americans.Sci Transl Med. 2016; 8 (:364ra151-364ra151. https://doi.org/10.1126/scitranslmed.aag2367)
Dietz H. FBN1-related Marfan syndrome. GeneReviews [internet]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, eds. University of Washington; Updated February 17, 2022. Accessed February 17, 2022. https://www.ncbi.nlm.nih.gov/books/NBK1335/.
Loeys BL, Dietz HC. Loeys-Dietz syndrome. GeneReviews [internet]. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. University of Washington; Updated March 1, 2018. Accessed March 1, 2018. https://www.ncbi.nlm.nih.gov/books/NBK1133/.
- Aneurysm syndromes caused by mutations in the TGF-β receptor.N Engl J Med. 2006; 355: 788-798https://doi.org/10.1056/NEJMoa055695
- Hereditary influence in thoracic aortic aneurysm and dissection.Circulation. 2016; 133: 2516-2528https://doi.org/10.1161/CIRCULATIONAHA.116.009762
- Nonsyndromic thoracic aortic aneurysms and dissections-is screening possible?.Semin Thorac Cardiovasc Surg. 2019; 31: 628-634https://doi.org/10.1053/j.semtcvs.2019.05.035
Byers PH. Vascular Ehlers-Danlos syndrome. GeneReviews [internet]. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. University of Washington. Updated February 21, 2019. Accessed February 21, 2019. https://www.ncbi.nlm.nih.gov/books/NBK1494/.
- Genetic basis of hereditary thoracic aortic aneurysms and dissections.J Cardiol. 2019; 74: 136-143https://doi.org/10.1016/j.jjcc.2019.03.014
- What is the clinical utility of genetic testing?.Genet Med. 2006; 8: 448-450https://doi.org/10.1097/01.gim.0000227935.26763.c6
- SHRINE: enabling nationally scalable multi-site disease studies.PLoS One. 2013; 8e55811https://doi.org/10.1371/journal.pone.0055811
- The impact of whole-genome sequencing on the primary care and outcomes of healthy adult patients: a pilot randomized trial.Ann Intern Med. 2017; 167: 159-169https://doi.org/10.7326/M17-0188
- Returning genomic results in a Federally Qualified Health Center: the intersection of precision medicine and social determinants of health.Genet Med. 2020; 22: 1552-1559https://doi.org/10.1038/s41436-020-0806-5
Article info
Publication history
Published online: August 09, 2022
Accepted:
July 4,
2022
Received in revised form:
July 4,
2022
Received:
March 6,
2022
Footnotes
Alborz Sherafati and Omar Elsekaily contributed equally.
Identification
Copyright
© 2022 Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.
