Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

“…With regard to additional genetic factors impacting expressivity, we assessed the impact of more common polygenic variation on carriers of monogenic variants and found significant contributions for both high HDL cholesterol and high triglyceride levels (P<0.05). These results add to a growing body of research supporting a significant polygenic contribution to monogenic risk 7,39,48,49 . As such analyses were restricted to carriers of monogenic variants, power was limited, and it will be important to investigate in even larger datasets.…”

Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia

“…An increased CVD risk, however, was not detected for the fraction of mutation negative patients in that same study. 47 Paquette et al reported similar results using a genetic risk score comprised of 192 SNPs associated with coronary artery disease (CAD) which were found to be strongly associated with CVD events in 725 FH mutation positive patients. 48 In clinical practice a score like this could be used for screening for "general CVD Iacocca & Hegele et al (2017) 51,52 leads to analogous conclusions.…”

Widening the spectrum of genetic testing in familial hypercholesterolaemia: Will it translate into better patient and population outcomes?

“…In a registry-based prospective study of 626 patients with at least "possible" FH, as determined by the commonly used Dutch Lipid Clinic Network Score, patients with mutation-positive FH and a polygenic risk score ≥ 80th percentile had the greatest increase in risk, followed by those with mutation-positive FH and no increase in the polygenic risk score (Figure 3). 77 Mutation-negative patients with polygenic hypercholesterolaemia alone were not at increased risk when compared with patients with neither finding. In cascade screening, patients without an FH phenotype may have similarly high polygenic scores to the index case.…”