Cardiogenetic testing at scale: the TruGenome Cardiovascular Disease Test and CardioSeq Clinical Trial

Introduction

Cardiovascular disease has long been a leading cause of morbidity and mortality, making it a priority in clinical care. Great strides have been made in understanding how genetic variation can cause or contribute to the development of cardiovascular disease (CVD), with next-generation sequencing greatly accelerating research and understanding. Today, a broad range of CVD diagnoses have been linked to genetic variants, including aortopathy, arrhythmia, cardiomyopathy, dyslipidemia, and coronary and peripheral arterial disease.

The clinical benefits of genetic testing in CVD are widely recognized, and professional societies recommend genetic testing for a broad swath of CVD patients and their family members.^1,2 Benefits can span all stages of life, from risk prediction and preventative care in early life, through diagnosis, treatment selection, and disease prognostication.³ By providing insights into the mechanisms of disease, genetic test results can prompt immediate changes in clinical care, including access to precision treatments such as enzyme replacement therapy or life-saving implantable cardioverter defibrillator (ICD) placement.^1,4,5,6 With more clinical trials requiring genetic testing for patient selection and several gene therapies for specific forms of CVD in development, an increase in genetic testing for patients with CVD is critical to further enable the discovery of novel treatments and move cardiology forward into an era of precision care.

Furthermore, cardiology as a clinic or service line is often the greatest contribution of procedural margin for a hospital or health system. The impact of emerging therapeutic opportunities, clinical trial participation, cascade testing and screening of at-risk relatives, and personalized care are all benefits of genomic-informed cardiovascular care to not only the patient's health outcome but the health system's growth and competitive business advantage.

Yet today, genetic testing remains profoundly underutilized across multiple cardiovascular conditions. Recent studies examining real-world testing practices in large patient populations report that only about 1.1% of CVD patients underwent genetic testing, despite professional guidelines and standards for testing.^7,8 One factor that may contribute to this gap is that cardiologists report a lack of confidence with ordering and interpreting genetic test results. With a multitude of test options on the market—from single gene tests, to multi-gene panels, to exome or genome testing—clinicians can find it difficult to navigate this piecemeal landscape and make the best testing choices for their patients.

The TruGenome^TM Cardiovascular Disease Test and CardioSeq Clinical Trial

To address this gap, we aimed to create a single, optimized, pan-cardiovascular disease genomic test to serve the testing needs of routine cardiology clinic patients. The TruGenome^TM Cardiovascular Disease Test is a laboratory developed test designed and validated by Illumina Laboratory Services (ILS), a CLIA-certified, CAP-accredited clinical laboratory at Illumina. The TruGenome^TM Cardiovascular Disease Test is a comprehensive panel test run on a whole-genome sequencing backbone. It has not been cleared or approved by the U.S. Food and Drug Administration. This test features a streamlined analysis pipeline with return of results across: (1) diagnostic variants (variants classified as likely pathogenic or pathogenic) in >200 high-confidence genes linked to monogenic CVD including aortopathy, arrhythmia, dyslipidemia, heart failure, and cardiomyopathy, (2) four common risk alleles for conditions with implications for clinical CVD care, (3) diagnostic variants in 35 non-CVD genes deemed medically actionable and recommended for return by the American College of Medical Genetics and Genomics as secondary findings,⁹ (4) 65 functional alleles from 10 high-impact pharmacogenes with broad medical management implications, and (5) a population-aware polygenic risk score to identify individuals at increased risk of coronary artery disease (offered by Allelica, Inc. and returned as a research report). By using a whole-genome sequencing approach, this test is able to detect—in a single assay—a broad range of variants including single nucleotide variants (SNVs), small indels, and copy number variants (CNVs), as well as a range of causal variants that may be missed by other approaches, such as mitochondrial variants, repeat expansions, and common chromosomal aneuploidies linked to CVD.¹⁰

To examine the clinical impacts of comprehensive genomic testing in a community cardiology clinic, we partnered with Dr. David Lanfear, a practicing advanced heart failure and transplant cardiologist and clinician scientist at Henry Ford Health, to conduct the CardioSeq Clinical Trial, a prospective, single-center, open-label study. Cardiology patients (n=1000) presenting with one or more CVD diagnoses were enrolled and received genetic testing using the TruGenome^TM Cardiovascular Disease Test. The study measured three primary outcomes: (1) rate of positive results for each of the five test components, (2) changes in clinical management, a proxy for clinical utility, and (3) physician and patient experiences.

Diagnostic performance and test yield

Across the cohort, 76 diagnostic variants, classified as either likely pathogenic or pathogenic, were reported to 74 patients, with two patients receiving two CVD molecular diagnoses each. Thus, the cohort-wide monogenic CVD yield was 7.4% (Figure 1). Of the 74 positive reports, 63 (85.1%) included a finding in a gene having guidelines for medical actionability.⁹ Additionally, 111 risk allele findings were reported to 109 patients, including two patients with two risk alleles each, for a yield of 10.9% (Figure 1).

Most patients (n=966) opted to receive findings from a short list of medically actionable genes recommended by the ACMG but not related to CVD included in their clinical reports, and 14 secondary findings, mostly related to hereditary cancer predisposition, were reported to 14 individuals, a yield of 1.4%. Pharmacogenomic findings were nearly universal in the cohort (99.1%) with only nine patients (0.9%) lacking a pharmacogenomic finding. An elevated polygenic risk score (PRS) indicating  2-fold greater risk of coronary artery disease was reported to 44 patients (4.4%). In total, 215 patients (21.5% of the cohort) received one or more findings associated with cardiovascular disease: a diagnostic variant in one of the >200 genes associated with monogenic CVD, a CVD risk allele, and/or elevated CAD PRS. Among them were 20 patients (2.0%, Figure 1) who received more than one finding.

Types of variants detected

The 76 reported variants associated with monogenic CVD were found in 30 unique genes, with 16 patients (21.6% of positive reports) having a finding in the TTR gene associated with hereditary transthyretin amyloidosis which can cause cardiomyopathy or cardiac conduction blocks¹¹ (two unique variants), 14 patients (18.9% of positive reports) having a finding in the TTN gene associated with cardiomyopathy¹² (14 unique variants), and eight patients (10.8% of positive reports) having a variant in the LDLR gene associated with familial hypercholesterolemia¹³ (eight unique variants). Most variants were small variants (n=71), including 54 SNVs, 12 deletions, and five insertions. Also, two repeat expansion disorders (myotonic dystrophy type 1 and type 2), one copy number variant (CNV) in the DMD gene, associated with Duchenne muscular dystrophy, one mitochondrial disease variant associated with Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes (MELAS), and one case of mosaic Turners Syndrome (monosomy X) were reported (Figure 2). Interestingly, eight atypical genetic findings suggestive of hematological malignancy were discovered incidentally during analyses of the clinical genome data. Together, these findings highlight the ability of TruGenome^TM Cardiovascular Disease Test to detect a wide variety of variants, some of which may be missed by targeted testing approaches.

Identification of presymptomatic risk of disease and test concordance

Beyond its role in diagnosis and prognostication, genetic testing can identify patients at risk of developing disease, allowing for preventative care and improved clinical outcomes. For each monogenic finding and elevated PRS reported in the CardioSeq cohort (n=76 and n=44 findings, respectively), we examined patient records to determine whether the patient already expressed the disease associated with their genetic finding (i.e., concordance between existing clinical diagnoses and genetic findings), or rather, if the patient was not yet diagnosed with the disease. As expected, we found rates of prevalent disease trended higher in patients with genetic findings compared to patients without findings, except for aortopathy, where sample size was small (n=1). This pattern was especially strong for heart failure/cardiomyopathy and coronary/peripheral artery disease, where significant differences in disease prevalence were found (Figure 3).

Through these analyses, we identified 34 patients (3.4%) at genetic risk of developing a cardiovascular disease or diseases they were not diagnosed with at the time of testing, highlighting the power of a comprehensive, GS approach for identifying presymptomatic disease risk.

Strengths of genome testing

A meaningful advantage of GS is offering a single, comprehensive test for patients with a disease known to have genetic causes. CVD disease presentations can be heterogeneous and overlapping, making it difficult to select the appropriate focused panel test (or tests) and straining the resources of clinicians and cardiology clinics to choose and implement the right test.

For example, arrhythmia can be an early symptom of heritable cardiomyopathy.¹⁴ Panel testing focused on arrhythmia in these patients is likely to miss the causal variant, leading to false negative test results and a missed opportunity for preventative care. Indeed—combining monogenic and PRS findings—we identified 34 CardioSeq Clinical Trial patients (3.4% of the cohort) who were at risk of developing a CVD diagnosis or diagnoses they did not already have. These data illustrate the real-world prevalence of disease heterogeneity or atypical presentations and the potential benefits of comprehensive testing.

Using a whole-genome approach has broader advantages for laboratories or institutions. For clinical laboratories offering multiple genetic tests (e.g., rare genetic disease, hereditary cancer, cardiovascular disease, carrier screening and newborn sequencing), a whole-genome backbone provides a single, streamlined wet laboratory workflow to support multiple indications for testing handled by differences in tertiary analysis steps. Additionally, with patient consent, laboratories associated with larger precision medicine research programs may push data into research pipelines.

Implementing comprehensive genome-based CVD testing

Illumina Laboratory Services (ILS) is an accredited clinical laboratory staffed by clinical geneticists, genetic counselors, bioinformaticians and scientists. The ILS team supports both clinical and research genetic testing across Illumina’s broad product portfolio. The ILS TruGenome^TM Cardiovascular Disease Test service is a laboratory developed test that was designed and validated by ILS, a CLIA-certified, CAP-accredited clinical laboratory. It has not been cleared or approved by the U.S. Food and Drug Administration. ILS aims to support Illumina customers through clinical test send out services and peer-to-peer engagement.  

Conclusion

Early data from the CardioSeq Clinical Trial demonstrate that the comprehensive TruGenome^TM Cardiovascular Disease Test delivers multifactorial genetic insights that may benefit patients at different stages of disease, from early identification of disease risk through clinical decision-making and management of disease. By developing a whole-genome based test that spans monogenic variants, risk alleles, pharmacogenes, and polygenic risk into a single test, the TruGenome^TM Cardiovascular Disease Test is poised to support individualized care for cardiology patients while also simplifying test ordering and laboratory workflows.

Learn More

To learn more about implementing the TruGenome^TM Cardiovascular Disease Test in your lab, or to start a partnership with ILS, contact an Illumina representative.

Resources

Test development manuscript.

GenomeWeb Webinar.

GenomeWeb Write-up

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