Development of a comprehensive cardiovascular disease genetic risk assessment test

Background Despite monogenic and polygenic contributions to cardiovascular disease (CVD), genetic testing is not widely adopted, and current tests are limited by the breadth of surveyed conditions and interpretation burden. Methods We developed a comprehensive clinical genome CVD test with semi-automated interpretation. Monogenic conditions and risk alleles were selected based on the strength of disease association and evidence for increased disease risk, respectively. Non-CVD secondary findings genes, pharmacogenomic (PGx) variants and CVD polygenic risk scores (PRS) were assessed for inclusion. Test performance was modeled using 2,594 genomes from the 1000 Genomes Project, and further investigated in 20 previously tested individuals. Results The CVD genome test is composed of a panel of 215 CVD gene-disease pairs, 35 non-CVD secondary findings genes, 4 risk alleles or genotypes, 10 PGx genes and a PRS for coronary artery disease. Modeling of test performance using samples from the 1000 Genomes Project revealed ∼6% of individuals with a monogenic finding in a CVD-associated gene, 6% with a risk allele finding, ∼1% with a non-CVD secondary finding, and 93% with CVD-associated PGx variants. Assessment of blinded clinical samples showed complete concordance with prior testing. An average of 4 variants were reviewed per case, with interpretation and reporting time ranging from 9-96 min. Conclusions A genome sequencing based CVD genetic risk assessment can provide comprehensive genetic disease and genetic risk information to patients with CVD. The semi-automated and limited interpretation burden suggest that this testing approach could be scaled to support population-level initiatives. ### Competing Interest Statement LMA, AJC, JL, JA, AM, AC, JPT, RR, CMB, KGG, RH, PM, BM, FM, AW, AH-V, ML, DL, DH, SSA, AK, SPS, EM and RJT were employees and/or shareholders of Illumina, Inc. when this work was completed. DEL is a consultant for Abbott Laboratories, ARMGO, Astra Zeneca, Illumina, Janssen, and Martin Pharmaceuticals, and has participated in clinical research from Akros, AstraZeneca, Bayer, Illumina, Janssen, Lilly, and Pfizer, and has a patent (held by Henry Ford Health) for a beta blocker polygenic score. ### Funding Statement This work was supported by Illumina, Inc. David E Lanfear's effort is supported in part by grants from the NIH (R01HL132154 and PM0MD017351). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional review board approval for activities involving human samples was received from WIRB-Copernicus Group (Protocol 20241866). Informed consent was not required. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. * ACMG : American College of Medical Genetics and Genomics AMP : Association for Molecular Pathology CVD : cardiovascular disease GDR : gene-disease relationship ICSL : Illumina Clinical Services Laboratory MAF : minor allele frequency GS : genome sequencing P : pathogenic LP : likely pathogenic