A pragmatic clinical trial of cascade testing for familial hypercholesterolemia

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 (FHg+) in LDLR, APOB, or PCSK9 and 73 probands without such a variant (FHg-). After direct contact by the study team, family members (FMs) of FHg+ probands could opt-in for genetic testing and FMs of FHgprobands were asked to provide a lipid profile. New cases were defined as presence of a pathogenic variant in FHg+ families and as low-density lipoprotein cholesterol >= 155 mg/dL in FHg- families. Results: Of 71 FHg+ probands seen by a genetic counselor, 52 consented and identified 253 FMs (111 consented and were tested, yielding 48 new cases). Of 101 FHg- 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 FHg+ than in FHg- 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. (c) 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Automated summary

This study compared the detection of new cases in familial hypercholesterolemia (FH) families with or without an identifiable monogenic etiology. The results showed a higher detection rate of new cases in families with a monogenic etiology, primarily due to a higher uptake and yield of cascade testing.