Mobile Menu

Underdiagnosis of monogenic heart and vascular diseases

Through performing whole-exome sequencing (WES), researchers have found that diagnoses for monogenic cardiovascular diseases (MCVDs) may have previously been missed.

Monogenic CVD

Monogenic diseases are individually rare but collectively quite common, posing a huge burden on families and society. They often present with severe clinical phenotypes that have high morbidity and mortality rates.

Monogenic CVDs encompass a wide range of phenotypes that result in coronary artery disease, heart failure, aortic dissection and/or malignant ventricular arrhythmias. There are an increasing number of treatments available that aim to alter disease progression and improve patient outcome. However, it is vital that the disease is recognised and diagnosed early to gain maximum benefit from these treatments.

Whole-exome sequencing

The increasing accessibility of whole-exome sequencing has enabled scientists and clinicians to determine the prevalence of pathogenic variants for monogenic diseases. In this study, published in the Journal of the American College of Cardiology, researchers sought to determine the prevalence of disease-causing variants associated with monogenic CVDs. They utilised the cardiac catheterization laboratory (CATHGEN) biorepository, where they sequenced the exomes of 8,574 individuals.

MCVD genes were identified by reviewing clinical genetic testing panels for cardiomyopathies, arrhythmias, connective tissue disorders and familial hypercholesterolemia and included genes for congenital heart disease and skeletal myopathies. The pathogenicity of the variants was determined using ClinVar. All candidate pathogenic (P) or likely pathogenic (LP) variants were then classified using the ACMG/AMP guidelines for variant classification. Electronic health records were reviewed to determine whether individuals harbouring P/LP variants were given a relevant diagnosis. Those who were not documented with the relevant diagnosis were classified into groups based on whether they represented missed diagnoses (unknown, unlikely, possible, probable or definite).

Prevalence of variants

In total, researchers found that over a quarter of their cohort carried at least 1 P/LP variant (n=2,361; 28%). Moreover, 4.5% (n= 389) of the overall cohort were predicted to be at risk of MCVD. An EHR review of 342 individuals who were predicted to develop disease revealed that 52 had been given the relevant clinical diagnosis. Most importantly, 149 individuals carrying P/LP were considered to have relevant MCVD phenotype. As a result, this meant that only 35% of individuals were diagnosed. The remaining 97 individuals that carried a P/LP variant had clinical expression of disease but were not given a diagnosis. These individuals represent a ‘missed opportunity’.

These results support greater use of genetic testing in patients being evaluated for CVDs. The team suggest that genetic testing should be guided by clinical, electrocardiographic and echocardiographic data. Identifying pathogenic variants early not only helps with the management of disease in the individual but is also important for cascade screening of other family members who may be at risk.

Image credit: Background vector created by starline –

More on these topics

Cardiovascular disease / Exome / Heart