Dataset Information

Phenotypic vs. genetic cascade screening for familial hypercholesterolemia: A case report.

ABSTRACT: One of the most common autosomal dominant disorders is familial hypercholesterolemia (FH), causing premature atherosclerotic cardiovascular diseases and a high risk of death due to lifelong exposure to elevated low-density lipoprotein cholesterol (LDL-C) levels. FH has a proven arsenal of treatments and the opportunity for genetic diagnosis. Despite this, FH remains largely underdiagnosed worldwide. Cascade screening is a cost-effective method for the identification of new patients with FH and the prevention of cardiovascular diseases. It is usually based only on clinical data. We describe a 48-year-old index patient with a very high LDL-C level without controlled guidelines-based medication, premature atherosclerosis, and a rare variant in the low-density lipoprotein receptor (LDLR) gene. Phenotypic cascade screening identified three additional FH relatives, namely the proband's daughter, and two young grandsons. The genetic screening made it possible to rule out FH in the proband's younger grandson. This clinical case demonstrates that genetic cascade screening is the most effective way of identifying new FH cases. We also first described in detail the phenotype of patients with a likely pathogenic variant LDLR-p.K223_D227dup.

SUBMITTER: Blokhina AV

PROVIDER: S-EPMC9453448 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phenotypic vs. genetic cascade screening for familial hypercholesterolemia: A case report.

Blokhina Anastasia V AV Ershova Alexandra I AI Meshkov Alexey N AN Kiseleva Anna V AV Klimushina Marina V MV Zharikova Anastasia A AA Sotnikova Evgeniia A EA Ramensky Vasily E VE Drapkina Oxana M OM

Frontiers in cardiovascular medicine 20220825

One of the most common autosomal dominant disorders is familial hypercholesterolemia (FH), causing premature atherosclerotic cardiovascular diseases and a high risk of death due to lifelong exposure to elevated low-density lipoprotein cholesterol (LDL-C) levels. FH has a proven arsenal of treatments and the opportunity for genetic diagnosis. Despite this, FH remains largely underdiagnosed worldwide. Cascade screening is a cost-effective method for the identification of new patients with FH and t ...[more]

PMID: 36093134

Similar Datasets

Project description:ImportanceFamilial hypercholesterolemia (FH) is the most common inherited cardiovascular disease and carries significant morbidity and mortality risks. Genetic testing can identify affected individuals, but some array-based assays screen only a small subset of known pathogenic variants.ObjectiveTo identify the number of clinically significant variants associated with FH that would be missed by an array-based, limited-variant screen when compared with next-generation sequencing (NGS)-based comprehensive testing.Design, setting, and participantsThis cross-sectional study compared comprehensive genetic test results for clinically significant variants associated with FH with results for a subset of 24 variants screened by a limited-variant array. Data were deidentified next-generation sequencing results from indication-based or proactive gene panels. Individuals receiving next-generation sequencing-based genetic testing, either for an FH indication between November 2015 and June 2020 or as proactive health screening between February 2016 and June 2020 were included. Ancestry was reported by clinicians who could select from preset options or enter free text on the test requisition form.Main outcomes and measuresNumber of pathogenic or likely pathogenic (P/LP) variants identified.ResultsThis study included 4563 individuals who were referred for FH diagnostic testing and 6482 individuals who received next-generation sequencing of FH-associated genes as part of a proactive genetic test. Among individuals in the indication cohort, the median (interquartile range) age at testing was 49 (32-61) years, 55.4% (2528 of 4563) were female, and 63.6% (2902 of 4563) were self-reported White/Caucasian. In the indication cohort, the positive detection rate would have been 8.4% (382 of 4563) for a limited-variant screen compared with the 27.0% (1230 of 4563) observed with the next-generation sequencing-based comprehensive test. As a result, 68.9% (848 of 1230) of individuals with a P/LP finding in an FH-associated gene would have been missed by the limited screen. The potential for missed findings in the indication cohort varied by ancestry; among individuals with a P/LP finding, 93.7% (59 of 63) of self-reported Black/African American individuals and 84.7% (122 of 144) of Hispanic individuals would have been missed by the limited-variant screen, compared with 33.3% (4 of 12) of Ashkenazi Jewish individuals. In the proactive cohort, the prevalence of clinically significant FH variants was approximately 1:191 per the comprehensive test, and 61.8% (21 of 34) of individuals with an FH-associated P/LP finding would have been missed by a limited-variant screen.Conclusions and relevanceLimited-variant screens may falsely reassure the majority of individuals at risk for FH that they do not carry a disease-causing variant, especially individuals of self-reported Black/African American and Hispanic ancestry.

Dataset Information

Phenotypic vs. genetic cascade screening for familial hypercholesterolemia: A case report.

Publications

Phenotypic vs. genetic cascade screening for familial hypercholesterolemia: A case report.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets