Enabling research translation:
generating clinical genetic reports to improve the management of cardiovascular disease


Heart disease is a leading cause of death and disability in Canada and worldwide, which largely results from the insidious process not being identified or treated until it is too late (1). This is best exemplified by patients with familial hypercholesterolemia (FH). FH is the most common autosomal dominant genetic disorder resulting from pathogenic genetic variants in the LDLR, APOB, and/or PCSK9 genes (~1 out of 225 people) (2). These genetic variants cause elevated low-density lipoprotein cholesterol, more commonly known as “bad cholesterol”, and significantly increase these patients’ risk of cardiovascular disease.

Our lab has developed a targeted next-generation sequencing assay that can accurately identify the presence of monogenic FH-causing variants or polygenic causes of hypercholesterolemia in patients with a clinical diagnosis of FH (3, 4). To realize the full value of this research, the results need to be fed back to the patients and their healthcare providers. However, this is currently recommended as best clinical practice for managing FH (5).

A pathogenic variant in LDLR, APOB, or PCSK9 can be identified in 30–80% of patients with clinically-diagnosed familial hypercholesterolemia (FH). Alternatively, ~20% of clinical FH is thought to have a polygenic cause. The cardiovascular disease (CVD) risk associated with polygenic versus monogenic FH is unclear. The objective of this study was to investigate the impact of genotype, including monogenic and polygenic causes of FH, on CVD risk among patients with clinically diagnosed FH. We hypothesized that FH patients with monogenic FH variants and elevated low-density lipoprotein cholesterol polygenic risk scores would have greater risk of CVD than patients in whom no causative variant is identified.

We will describe how we are using VarSeq® software to screen next-generation sequencing DNA results for for both monogenic and polygenic causes of FH. In addition, we will use FH as an example to demonstrate how the American College of Medical Genetics and Genomics/Association for Molecular Pathology joint guidelines for variant interpretation and classification can be easily applied to DNA sequencing data to generate meaningful clinical reports.

About the Presenter

Mark Trinder

Mark Trinder is an MD/Ph.D. student at the University of British Columbia, Canada working under the supervision of Dr. Liam Bruham. Mark’s research focuses on the interplay between the genetic regulation of lipoproteins (“good” and “bad” cholesterol) and inflammatory diseases such as sepsis and atherosclerosis. Sepsis is a systemic exaggerated host immune response to infection that has a high mortality rate, limited effective treatments, and is a considerable economic health care burden. The Brunham lab and collaborators at St. Paul’s Centre for Heart and Lung Innovation have observed that patients’ with low levels of high-density lipoprotein (HDL) have a poor sepsis prognosis. However, mechanistic understanding of why HDL levels are low in certain septic patients is unknown. Differences in sepsis parthenogenesis and outcomes have the potential to be explained by variations in human genetics. The findings of this work will provide insights into improved management and generation of better treatment options for sepsis.