A proof-of-concept study of cascade screening for Familial Hypercholesterolemia in the US, adapted from the Dutch model

Abstract

Background The Dutch cascade screening model for FH was the most successful of such programs in the world. It remains unclear whether aspects of the Dutch model (i.e. direct engagement with FH probands and relatives outside usual healthcare settings) are feasible in the US. This is especially important since prior attempts at cascade screening in the US have had very low screening rates (<10% of families screened). Methods We conducted a multi-site single-arm proof-of-concept study in which the US-based FH Foundation (a 501c3 research and advocacy organization) directly engaged with FH probands and relatives similar to the approach taken by the Dutch “Foundation for Tracing FH.” Results Eleven unrelated probands with genetically confirmed FH were enrolled. Mean age was 43 years; 82% were women, and 82% were of European ancestry. Prior to enrolling into the study, only 2 families (18% screening rate) were screened for FH with both lipid measurements and genetic testing. Two probands declined cascade screening due to fear over genetic discrimination. Nine total relatives engaged with the FH Foundation. Mean age was 43 years and 44% were women. Seven of those relatives (from 6 families; 55% screening rate) consented to be screened for FH with lipid measurement and genetic testing. The two additional relatives – men ages 39 and 49 – agreed to lipid measurements but not genetic testing, each noting he would like to think more about genetic testing. Conclusions Our proof-of-concept study demonstrates the feasibility of the FH Foundation engaging FH probands and their relatives outside the usual healthcare settings for cascade screening, similar to the Dutch model. We found only 18% of families had already been screened, and after engaging with the FH Foundation, 55% of families were willing to participate in cascade screening. These findings suggest the methods described here may improve cascade screening rates in the US.

Analysis of Rare Variants in Genes Related to Lipid Metabolism in Patients with Familial Hypercholesterolemia in Western Siberia (Russia)

“…In this study, the prevalence of detected "pathogenic" and "probably pathogenic" mutations was 47.5% among the analyzed probands with a phenotype of familial hypercholesterolemia from the Western Siberia region (Russia) and 85.7% among their tested children who also had a phenotype of familial hypercholesterolemia. As in other studies, this finding confirms the effectiveness of cascade genetic screening [45][46][47][48][49][50].…”

The Impact of Proband Indication for Genetic Testing on the Uptake of Cascade Testing Among Relatives

“…However, ongoing studies, such as the IMPACT-FH (Identification Methods, Patient Activation, and Cascade Testing for FH) study ( Campbell-Salome et al, 2021 ), are exploring strategies that increase the uptake of cascade testing in population-based screening programs. However, learnings from the diagnostic setting may provide some insights, including the availability of clinician-drafted letters ( Newson and Humphries, 2005 ; Suthers et al, 2006 ; Hadfield et al, 2009 ; Dilzell et al, 2014 ; Petersen et al, 2019 ; Kurian and Katz, 2020 ; Neuner et al, 2020 ), access to support from foundations focused on a single condition or clinical area ( Bell et al, 2015 ; Wald et al, 2016 ; McGowan et al, 2021 ), and access to educational materials that are easily shared outside of a clinical setting ( Kardashian et al, 2012 ; Petersen et al, 2019 ; Bowen et al, 2020 ; Jujjavarapu et al, 2021 ; Nazareth et al, 2021 ; Nitecki et al, 2021 ; Snir et al, 2021 ). When considering approaches to encouraging at-risk relatives to ultimately seek cascade testing, programs have been designed to offer cascade testing at reduced rates or at no-charge for relatives ( Aktan-Collan et al, 2007 ; Caswell-Jin et al, 2019 ; Courtney et al, 2019 ; Invitae, 2021 ).…”

Acceptability, Appropriateness, and Feasibility of Automated Screening Approaches and Family Communication Methods for Identification of Familial Hypercholesterolemia: Stakeholder Engagement Results from the IMPACT-FH Study

“…Cascade testing facilitated by direct contact for genomic risk conditions has been successful in other countries, but direct contact has not been widely implemented in the U.S. and cascade testing uptake has also been slow [ 24 , 36 , 37 ] as it is met with substantial implementation barriers [ 38 ]. A recent pilot study of cascade testing for FH in primary care practices in the U.S. found an approximate 50% uptake of cascade testing by relatives, but noted limitations in data collection due to data privacy issues [ 39 ].…”

“…A recent evidence review and other literature have also found that direct contact by healthcare clinicians is preferred by some individuals and is also effective [ 40 , 41 , 42 ]. Further, a recent pilot program has shown potential feasibility of direct contact [ 37 ]. Despite being effective and being viewed as a valuable program by our participants, the implementation of direct contact has not yet been widely adopted.…”