A pragmatic clinical trial of cascade testing for familial hypercholesterolemia

Abstract

Purpose: We compared new cases detected per index case in familial hypercholesterolemia (FH) families with or without an identifiable monogenic etiology.

Methods: We enrolled 52 FH probands with a pathogenic variant (FH^g+) in LDLR, APOB, or PCSK9 and 73 probands without such a variant (FH^g-). After direct contact by the study team, family members (FMs) of FH^g+ probands could opt-in for genetic testing and FMs of FH^g- probands were asked to provide a lipid profile. New cases were defined as presence of a pathogenic variant in FH^g+ families and as low-density lipoprotein cholesterol ≥155 mg/dL in FH^g- families.

Results: Of 71 FH^g+ probands seen by a genetic counselor, 52 consented and identified 253 FMs (111 consented and were tested, yielding 48 new cases). Of 101 FH^g- probands who received counseling, 73 consented and identified 295 FMs (63 consented and were tested, yielding 17 new cases). New case detection per index case was significantly greater in FH^g+ than in FH^g- families (0.92 vs 0.23), a result of higher cascade testing uptake (43.9 vs 21.4%) and yield (43.2 vs 27.0%) in the former.

Conclusion: New case detection rate was significantly higher in FH families with a monogenic etiology than in those without such an etiology owing to greater uptake and yield of cascade testing.

Trial registration: ClinicalTrials.gov NCT03640234.

Keywords: Cascade testing; Familial hypercholesterolemia; Monogenic; Polygenic; Variant.

Figure 1. Overview of study workflow for probands and family members.

FH^g+, familial hypercholesterolemia with a pathogenic variant; FH^g−, familial hypercholesterolemia without a pathogenic variant; LDL-C, low-density lipoprotein cholesterol; P°, primary; P/LP, pathogenic/likely pathogenic; S°, secondary.