Moving Genomics to Routine Care

Abstract

Background - Whole genome sequencing (WGS) costs are falling, yet, outside oncology, this information is seldom used in adult clinics. We piloted a rapid WGS (rWGS) workflow, focusing initially on estimating power for a feasibility study of introducing genome information into acute cardiovascular care. Methods - A prospective implementation study was conducted to test the feasibility and clinical utility of rWGS in acute cardiovascular care. Rapid WGS was performed on 50 adult patients with acute cardiovascular events and cardiac arrest survivors, testing for primary and secondary disease-causing variants, cardiovascular related pharmacogenomics, and carrier status for recessive diseases. The impact of returning rWGS results on short term clinical care of participants was investigated. The utility of polygenic risk scores (PRS) to stratify coronary artery disease (CAD) was also assessed. Results - Pathogenic variants, typically secondary findings, were identified in 20%, (95% CI, 11.7-34.3). About 60% (95% CI, 46.2-72.4) of participants were carriers for one or more recessive traits, most commonly in HFE and SERPINA1 genes. Although 64%, (95% CI, 50.1-75.9) of participants carried at least one pharmacogenetic variant of cardiovascular relevance, these were actionable in only 14%, (95% CI, 7-26.2). CAD prevalence among participants at the 95th percentile of PRS was 88.2%, (95% CI, 71.8-95.7). Conclusions - We demonstrated the feasibility of rWGS integration into the inpatient management of adults with acute cardiovascular events. Our pilot identified pathogenic variants in one out of five acute vascular patients. Integrating rWGS in clinical care will progressively increase actionability.

“One Brave Idea” Project Yields New Disease Pathways and Tools to Speed Up Heart Research

“…To close this gap, the team built a software program that embeds in existing electronic medical record platforms and helps identify individuals who may benefit from genetic analysis. 3 Given the limited clinical personnel available for such work, the team developed tools to empower patients to reach out to their families and engage them in care and research. The tool also provides a QR code with information about the condition that an individual's local clinician can use.…”

Patient and Clinician Perceptions of Precision Cardiology Care: Findings From the HeartCare Study

“…In general, patient-participants perceived genetic testing for CVD risk to be useful, on a scale from not at all useful (1) to extremely useful (6), for managing their health both now (median 5) and in the future (median 5; Table S1). While 76.8% of participants rated the usefulness the same both now and in the future, those who thought there would be a change in utility more frequently thought that it would increase rather than decrease (P<0.001).…”

“…1 With growing recognition of oligogenic and polygenic inheritance of many common cardiovascular conditions, genome-wide testing has become more relevant for diagnosis and management. Genome-wide testing, including whole genome sequencing, 2–5 expanded multi-gene panels, 6–8 and polygenic risk scores (PRS), 9,10 can inform differential diagnosis of diseases with clinical mimics, such as hypertrophic cardiomyopathy, and provide prognostic advantages for complex diseases that are influenced by multiple genes and gene variants, such as coronary artery disease. 7,11 Routine, clinic-based genetic screening can therefore be used to confirm molecular pathogenesis in patients with clinical symptoms and to detect preclinical disease, identifying individuals who would benefit from clinical surveillance.…”

Effect of prothrombin Belgrade mutation, causing antithrombin resistance, on fibrin clot properties

“…Prothrombin Belgrade mutation (c.1787G>A, p.Arg596Gln) was detected in two families in Serbia, with 10 members being heterozygous carriers, and six of them developing recurrent thrombotic disorders at a young age 4 . Prothrombin Belgrade mutation was also detected in American, Japanese, Chinese, and Indian population 5–8 . Apart from influencing thrombin‐antithrombin interactions, prothrombin Belgrade mutation impacts the sodium binding region, which is important for maintenance of hemostatic balance.…”

“…4 Prothrombin Belgrade mutation was also detected in American, Japanese, Chinese, and Indian population. [5][6][7][8] Apart from influencing thrombinantithrombin interactions, prothrombin Belgrade mutation impacts the sodium binding region, which is important for maintenance of hemostatic balance. Binding of sodium improves the procoagulant function of prothrombin due to the increased fibrinogen affinity, that is, affected by the presence of prothrombin Belgrade, and therefore, may lead to a disruption of normal coagulation.…”