Top Things to Know: Interpreting Incidentally Identified Variants in Genes Associated with Heritable CVD
Published: March 27, 2023
Prepared by Katherine A. Sheehan, PhD, Science and Medicine Advisor
- As genetic sequencing technologies become more affordable, accessible, and clinically useful, sequencing of the protein-coding exome and the full genome for purposes of research, clinical diagnostics and personal interest for consumers has grown.
- Along with the increased use of genetic sequencing for specific diagnostics, the identification of other genetic variants has also increased. These incidentally identified variants may be in genes that underlie monogenic cardiovascular disease (CVD) associated with high morbidity and mortality, such as familial dyslipidemias, thus issues surrounding their reporting, interpretation and clinical impact are critically important.
- This scientific statement provides guidance to users of diagnostic genetic testing to aid in determining the pathogenicity of incidentally identified variants in CVD-associated genes, along with the risk for disease penetrance they represent and next steps for incorporating this information into the evaluation and care of the patient and their family.
- A growing number of variants have been identified in CVD-associated genes which may be identified in a genetic test but in the absence of a corresponding CV phenotype or disease. Some clinically actionable genes relating to CVD that are associated with increased morbidity and mortality have evidence-based treatments available, yet some CVD-related genes are not as well characterized.
- Guidance is given on how to determine which identified variants may be likely to increase CVD risk and which may be more likely to be benign. This evaluation may require specialized clinical expertise which could impose a barrier to patient care.
- Pre-test genetic counseling and informed consent is critical to inform the patient of the type of incidental results that may be generated or communicated. Counseling can provide information on overall benefits, risks and limitations of the sequencing, potential implications for family members, financial costs, and other information about the state of the science that will inform decision-making.
- A specific framework for the interpretation of incidentally identified variants in CVD-associated genes is presented which integrates the likelihood that an identified variant is disease-associated with the likelihood that the individual has the disease associated with that variant.
- Clinical management and follow-up planning is described for persons with identified incidental CVD gene variants, even in the absence of disease. Longitudinal follow-up is important not only to the care of the patient, but as science continues to advance, understanding of the variant’s likelihood to result in disease is improved and may impact clinical care. The availability of genome-wide association studies in diverse populations is one of these areas of advancement.
- The increased use of genetic testing in research, clinical and consumer settings has expanded the incidental identification of variants in genes associated with CVD, leading to a need for clinician guidance in how to report and interpret these variants, as well as for patient care.
- For clinicians whose patients have incidentally identified CVD-associated gene variants, this statement provides guidance encompassing determination of variant pathogenicity, counseling for the patient and family members, and next steps in care and follow-up.
Citation
Landstrom AP, Chahal AA, Ackerman MJ, Cresci S, MD; Milewicz DM, Morris AA Sarquella-Brugada G, Semsarian C, Shah SH, Sturm AC; on behalf of the American Heart Association Data Science and Precision Medicine Committee of the Council on Genomic and Precision Medicine and Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Hypertension; Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Peripheral Vascular Disease; and Stroke Council. Interpreting incidentally identified variants in genes associated with heritable cardiovascular disease: a scientific statement from the American Heart Association [published online ahead of print March 27, 2023]. Circ Genom Precis Med. doi: 10.1161/HCG.0000000000000092