Identification of Undetected Monogenic Cardiovascular Disorders

Abstract

Background: Monogenic diseases are individually rare but collectively common, and are likely underdiagnosed.

Objectives: The purpose of this study was to estimate the prevalence of monogenic cardiovascular diseases (MCVDs) and potentially missed diagnoses in a cardiovascular cohort.

Methods: Exomes from 8,574 individuals referred for cardiac catheterization were analyzed. Pathogenic/likely pathogenic (P/LP) variants associated with MCVD (cardiomyopathies, arrhythmias, connective tissue disorders, and familial hypercholesterolemia were identified. Electronic health records (EHRs) were reviewed for individuals harboring P/LP variants who were predicted to develop disease (G+). G+ individuals who did not have a documented relevant diagnosis were classified into groups of whether they may represent missed diagnoses (unknown, unlikely, possible, probable, or definite) based on relevant diagnostic criteria/features for that disease.

Results: In total, 159 P/LP variants were identified; 2,361 individuals harbored at least 1 P/LP variant, of whom 389 G+ individuals (4.5% of total cohort) were predicted to have at least 1 MCVD. EHR review of 342 G+ individuals predicted to have 1 MCVD with sufficient EHR data revealed that 52 had been given the relevant clinical diagnosis. The remaining 290 individuals were classified as potentially having an MCVD as follows: 193 unlikely (66.6%), 50 possible (17.2%), 30 probable (10.3%), and 17 definite (5.9%). Grouping possible, probable, definite, and known diagnoses, 149 were considered to have an MCVD. Novel MCVD pathogenic variants were identified in 16 individuals.

Conclusions: Overall, 149 individuals (1.7% of cohort) had MCVDs, but only 35% were diagnosed. These patients represents a "missed opportunity," which could be addressed by greater use of genetic testing of patients seen by cardiologists.

Keywords: amyloidosis; exome sequencing; genetics; monogenic diseases.

Figure 1.. Identification and selection of pathogenic/likely pathogenic variants in the CATHGEN cohort.

In total, 49,831 variants were identified in 155 genes and 159 P/LP variants were utilized after annotation using the ACMG/AMP guidelines (Left). ACMG/AMP classification of the novel null variants in individuals with a clear clinical phenotype revealed 16 novel pathogenic variants (Right).

Figure 2.. Unique pathogenic/likely pathogenic variants identified in each gene.

The bars represent the number of P/LP variants identified in each gene, and they were colored according to the respective phenotype the gene is associated with.

Figure 3.. Genes mutated in individuals clinically diagnosed and individuals at risk of developing a monogenic disease but not diagnosed.

(A) Bar plot illustrating the 52 individuals who were given the relevant clinical diagnosis and the respective gene that was mutated. (B) Bar plot illustrating the 290 individuals at risk for developing a MCVD, and the respective gene that was mutated. Abbreviations as in Central Illustration.

Central Illustration.. Individuals diagnosed and potentially missed diagnoses.

Flow chart (left) illustrating the number of individuals harboring ≥1 P/LP variant, the number of individuals predicted to develop ≥1 MCVDs, and the number of individuals with the relevant clinical diagnosis. Barplot (right) illustrating the proportions of undiagnosed patients with their likelihood of a missed diagnosis. Abbreviations: P/LP: Pathogenic/Likely Pathogenic; MCVD: Monogenic Cardiovascular Disease; HH: Hereditary Hemochromatosis; HeFH: Heterozygous Familial Hypercholesterolemia; AS: Aortic Stenosis; DMD/BMD: Duchenne/Becker Muscular Dystrophy; EDS: Ehler-Danlos Syndrome