CLINICAL GENOME SEQUENCING IN ROUTINE CARDIOLOGY: INITIAL FINDINGS OF THE CARDIOSEQ STUDY
Recommended Citation
Lanfear DE, Lowry J, Amendola L, Trepanier A, Aurora L, Ferrari H, Cabral W, Kesari A, Rajkumar R, Chawla A, Coffey A, Hostin D, Huertas-Vazquez A, Perry D, Longoni M, Taft R. CLINICAL GENOME SEQUENCING IN ROUTINE CARDIOLOGY: INITIAL FINDINGS OF THE CARDIOSEQ STUDY. J Am Coll Cardiol 2025; 85(12):1364.
Document Type
Conference Proceeding
Publication Date
4-1-2025
Publication Title
J Am Coll Cardiol
Keywords
adult, African American, aged, allele, cardiomyopathy, cardiovascular disease, cardiovascular risk, Caucasian, clinical trial, cohort analysis, conference abstract, controlled study, coronary artery disease, diagnosis, diagnostic value, dyslipidemia, female, genetic disorder, genetic risk, genetic screening, genetic variability, heart arrhythmia, heart failure, human, major clinical study, male, peripheral arterial disease, pharmacogenetic variant, phenotype, race, risk factor
Abstract
Background: Cardiovascular disease (CVD) is multifactorial and includes monogenic and polygenic contributors to onset and severity. Clinical genetic testing in practice seldom meets guideline recommendations, in part due to test limitations, disease heterogeneity and uncertainty about the utility of positive findings. The CardioSeq study was designed to evaluate the diagnostic yield and clinical impact of comprehensive clinical genome sequencing (cGS) spanning hundreds of genes and genetic disorders, risk factors and potential care modifiers in patients presenting with CVD. Methods A prospective, open-label, single-center clinical trial was conducted at Henry Ford Health. Inclusion required a diagnosis of at least one among: cardiomyopathy or heart failure, aortopathy, arrhythmia, coronary or peripheral artery disease, and/or dyslipidemia. The cGS test included 215 CVD-associated genes, 4 common genetic variants associated with increased CVD risk, 35 optional non-CVD ACMG secondary findings genes, pharmacogenomic variants and a coronary artery disease (CAD) PRS. Results Of the 1,000 participants who received cGS testing, 501 were assigned male sex at birth (median age 69, IQR 61-75) and 499 were assigned female (median age 70, IQR 62-76). The most common self-reported races were white (57.9%) and African American (39.2%). Cardiomyopathy or heart failure accounted for 33.5% of the entire cohort. A total of 74 participants received a monogenic finding, roughly half of which were due to variants in three genes: TTR (n = 16, 21.6%), TTN (n = 14, 18.9%), and LDLR (n = 8, 10.8%). The TTR p.Val142Ile variant accounted for 20.3% of positive cases. Unadjusted diagnostic yield was highest in African American cases (11.5%). Risk allele findings were reported in 10.1% of study participants, secondary findings in 1.4%, and pharmacogenomic findings in <99%. An elevated CAD PRS was reported in 4.6% of participants. Conclusion A single comprehensive cGS test can provide useful diagnostic and genetic risk data across a broad range of CVD phenotypes and genetic ancestries. The investigation of the impact of cGS findings on clinical management is ongoing and will be reported at CardioSeq study completion.
Volume
85
Issue
12
First Page
1364
