Genetic insights into cardiomyopathy: initial findings of the CardioSeq study
L Aurora, A Huertas-Vazquez, J Lowry, L Amendola, A Trepanier, H Ferrari, W Cabral, D Hostin, H Metz, D Perry, M Longoni, R Taft, K Hatchell, D LanfearAbstract
Background
The development of cardiovascular disease (CVD) is in part genetically determined and clinical practice guidelines recommend genetic testing for suspected heritable CVDs including cardiomyopathies. Heart failure (HF)/cardiomyopathy (CM) syndromes are high prevalence, with high morbidity and mortality, and are common indications for genetic testing, yet testing rates remain low. To try to mitigate factors contributing to poor uptake of genetic testing, we performed the CardioSeq trial utilizing a comprehensive genetic test designed for routine use in cardiology clinic.
Purpose
The CardioSeq trial evaluated the diagnostic yield and clinical impact of a comprehensive clinical genome sequencing test (cGS) in ambulatory patients with CVD. Here we describe the detailed results of the CardioSeq trial specific to HF and CM.
Methods
A prospective, open-label, single-center clinical trial was conducted at a US-based integrated health care system. Inclusion required the patient to have an appointment in cardiology clinic and a diagnosis of at least one of the following conditions: aortopathy, arrhythmia, HF/CM, coronary or peripheral artery disease (CAD), or dyslipidemia. The CLIA/CAP certified cGS test included 215 CVD-associated genes, 4 common variants associated with increased CVD risk, 35 (optional) non-CVD ACMG secondary findings genes, 65 pharmacogenomics variants, and a CAD polygenic risk score. Significance was evaluated using tests of proportions.
Results
A total of 1000 participants completed the trial, of which 335 had a HF or CM diagnosis. Among these, 147 were female (44%), average age was 66 years, and self-reported race was white in 50.1% and black in 47.8%. HF/CM patients typically had comorbid cardiac diagnoses, averaging 1.8 additional CVD conditions. Of 335 HF/CM participants, 45 participants (13.4%) received at least one CVD monogenic finding, roughly 3 times the rate among non-HF/CM participants (29 of 665, 4.4%; p<0.000001). Among HF/CM participants risk allele findings were reported in 44 (13.1%), and ACMG secondary (non-CVD) findings in 1.8%. In total, 85 (25.4%) of HF/CM participants vs. 91 (13.7%) in the non-HF participants received either a monogenic or risk allele result related to CVD (p=0.000007). Patients with reduced ejection fraction (EF <=49%), trended towards higher total yield (monogenic or risk allele) when compared to those with normal EF (>=50%) (29.7% vs 20.7%, p=0.08). Among those with reduced EF, variants in TTN and TTR accounted for 59% of the monogenic findings. For those with normal EF, findings were more evenly distributed with TTN accounting for 17% and MYBPC3, MYH7, PKP2, and TTR each accounting for 11%.
Conclusions
In this real-world cohort, roughly 1 in 4 participants with HF/CM undergoing genetic testing received a positive monogenic or risk allele result. These data underscore the clinical value of comprehensive cGS, particularly in those with HF/CM.