Utility and Limitations of Genetic Testing in the Routine Care of Cardiovascular Disease Patients in a General Hospital

Abstract

Genetic diagnosis is becoming more prevalent in the routine care of cardiovascular disease (CVD) but is still limited to specialized institutions. Therefore, general cardiologists are also expected to acquire fundamental knowledge for incorporating genomics into the clinical practice of inherited to multifactorial CVDs. To accomplish this, the present study evaluated the utility and limitations of genetic testing in a general hospital setting.We examined 2 clinical issues: 1) the diagnostic potential of genetic tests for known inherited CVDs across 4 disease entities, i.e., familial hypercholesterolemia (FH), hypertrophic cardiomyopathy (HCM), suspected lethal arrhythmia, and aortic aneurysm/dissection (total n = 84) and 2) the genetic components associated with 2 multifactorial pathologies, cardiac hypertrophy and atrial fibrillation (AF), through a case-control study (total n = 594). We first performed targeted gene panel tests or whole-exome sequencing to identify causative gene variants for inherited CVDs; this yielded a positive test rate of 14 to 40%. The diagnosis rate for FH increased to 70% if strict eligibility criteria were adopted. The diagnosis rate for HCM also markedly increased by modifying the interpretation criteria for genetic variant pathogenicity. Furthermore, we performed gene-based burden tests and polygenic risk score (PRS) calculations for cardiac hypertrophy and AF. For example, the PRS-based genetic risk was significantly increased in early-onset (≤ 60 years) AF compared to non-AF controls (per-SD odds ratio in standardized PRS: 1.83, P = 2.6 × 10^-4).Genetic tests for CVDs may complement the diagnosis based on traditional laboratory-based diagnostics, although the currently limited capabilities of variant interpretation necessitate careful attention.

Keywords: Genetic diagnosis; Polygenic risk score; Rare variant.