Improving the yield of genetic testing in familial hypercholesterolaemia

Ajufo, Ezim; Cuchel, Marina

doi:10.1093/eurheartj/ehw166

Cited by 6 publications

(7 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Compared with patients with elevated LDL cholesterol (LDL-C) levels and no FH-associated variant, those with a monogenic FH-associated variant have an approximately 2- to 3.5-fold increased risk of CVD . However, in many individuals with a phenotype of clinical FH, a monogenic FH-associated variant cannot be identified . These individuals may have a polygenic, environmental, or unknown monogenic cause for their hypercholesterolemia.…”

Section: Introductionmentioning

confidence: 99%

Association of Monogenic vs Polygenic Hypercholesterolemia With Risk of Atherosclerotic Cardiovascular Disease

2020

View full text Add to dashboard Cite

IMPORTANCE Monogenic familial hypercholesterolemia (FH) is associated with lifelong elevations in low-density lipoprotein cholesterol (LDL-C) levels and increased risk of atherosclerotic cardiovascular disease (CVD). However, many individuals with hypercholesterolemia have a polygenic rather than a monogenic cause for their condition. It is unclear if a genetic variant for hypercholesterolemia alters the risk of CVD. OBJECTIVES To assess whether a genetic variant for hypercholesterolemia alters the risk of atherosclerotic CVD and to evaluate how this risk compares with that of nongenetic hypercholesterolemia. DESIGN, SETTING, AND PARTICIPANTS In this genetic-association, case-control, cohort study, individuals aged 40 to 69 years were recruited by the UK Biobank from across the United Kingdom between March 13, 2006, and October 1, 2010, and followed up until March 31, 2017. Genotyping array and exome sequencing data from the UK Biobank cohort were used to identify individuals with monogenic (LDLR, APOB, and PCSK9) or polygenic hypercholesterolemia (LDL-C polygenic score >95th percentile based on 223 single-nucleotide variants in the entire cohort). The data were analyzed from July 1, 2019, to December 30, 2019. MAIN OUTCOMES AND MEASURES The study investigated the association of genotype with the risk of coronary and carotid revascularization, myocardial infarction, ischemic stroke, and all-cause mortality among the overall study population and among participants with monogenic FH (n = 277), polygenic hypercholesterolemia (n = 2379), or hypercholesterolemia with undetermined cause (n = 2232) at comparable levels of LDL-C measured at study enrollment. RESULTS For the 48 741 individuals with genotyping array and exome sequencing data, the mean (SD) age was 56.6 (8.0) years, and 54.5% were female (n = 26 541 of 48 741). A monogenic FH variant for hypercholesterolemia was found in 277 individuals (0.57%, 1 in 176 individuals). Participants with monogenic FH were significantly more likely than those without monogenic FH to experience an atherosclerotic CVD event at 55 years or younger (17 of 277 [6.1%] vs 988 of 48 464 [2.0%]; P < .001). Compared with the general population, both monogenic and polygenic hypercholesterolemia were associated with an increased risk of CVD events. Moreover, among individuals with comparable levels of LDL-C, both monogenic (hazardratio,1.93;95%CI,1.34-2.77;P < .001)andpolygenichypercholesterolemia(hazardratio,1.26; 95% CI, 1.03-1.55; P = .03) were significantly associated with an increased risk of CVD events compared with the risk of such events in individuals with hypercholesterolemia without an identified genetic cause. CONCLUSIONS AND RELEVANCE The findings of this study suggest that among individuals with hypercholesterolemia, genetic determinants of LDL-C levels may impose additional risk of CVD. Thus, understanding the possible genetic cause of hypercholesterolemia may provide important prognostic information to treat patients.

show abstract

Section: Introductionmentioning

confidence: 99%

Association of Monogenic vs Polygenic Hypercholesterolemia With Risk of Atherosclerotic Cardiovascular Disease

2020

View full text Add to dashboard Cite

show abstract

“…Screening for genetic mutations was therefore recommended as standard of care for patients with definite or probable FH by an international Expert Consensus Panel 9 . However, the diagnostic yield of these screening programs is low 28 , ranging between 20 and 80% 29 , as a high number of suspected patients suffer from polygenic conditions 9 . Thus, the development of robust approaches that can contribute to increase this yield is critical to support a widespread use of FH genetic testing, with a considerable reduction of the resulting burden on health systems.…”

Section: Discussionmentioning

confidence: 99%

Machine learning modelling of blood lipid biomarkers in familial hypercholesterolaemia versus polygenic/environmental dyslipidaemia

Correia

Kagenaar

Schalkwijk

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Familial hypercholesterolaemia increases circulating LDL-C levels and leads to premature cardiovascular disease when undiagnosed or untreated. Current guidelines support genetic testing in patients complying with clinical diagnostic criteria and cascade screening of their family members. However, most of hyperlipidaemic subjects do not present pathogenic variants in the known disease genes, and most likely suffer from polygenic hypercholesterolaemia, which translates into a relatively low yield of genetic screening programs. This study aims to identify new biomarkers and develop new approaches to improve the identification of individuals carrying monogenic causative variants. Using a machine-learning approach in a paediatric dataset of individuals, tested for disease causative genes and with an extended lipid profile, we developed new models able to classify familial hypercholesterolaemia patients with a much higher specificity than currently used methods. The best performing models incorporated parameters absent from the most common FH clinical criteria, namely apoB/apoA-I, TG/apoB and LDL1. These parameters were found to contribute to an improved identification of monogenic individuals. Furthermore, models using only TC and LDL-C levels presented a higher specificity of classification when compared to simple cut-offs. Our results can be applied towards the improvement of the yield of genetic screening programs and corresponding costs.

show abstract

“…An important question is how this technology can best be applied in clinical practice, and the answer may differ in relation to the reasons for performing genetic analysis. Cascade screening in FH is generally initiated by analysis of lipid levels, clinical status and exclusion of secondary hyperlipidaemias, and establishment of a genetic diagnosis is considered to be of value in the early work-up of a family [3,4,7,8,27,28]. If the goal is to identify a causative mutation in the three classical FH genes, LDLR, APOB and PCSK9, initial genotyping based on a population-related panel would be diagnostic in~2/3 of the patients without utilizing NGS.…”

Section: Discussionmentioning

confidence: 99%

Founder effects facilitate the use of a genotyping‐based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia

et al. 2021

View full text Add to dashboard Cite

Aim To investigate whether genotyping could be used as a cost‐effective screening step, preceding next‐generation sequencing (NGS), in molecular diagnosis of familial hypercholesterolaemia (FH) in Swedish patients. Methods and results Three hundred patients of Swedish origin with clinical suspicion of heterozygous FH were analysed using a specific array genotyping panel embedding 112 FH‐causing mutations in the LDLR, APOB and PCSK9 genes. The mutations had been selected from previous reports on FH patients in Scandinavia and Finland. Mutation‐negative cases were further analysed by NGS. In 181 patients with probable or definite FH using the Dutch lipid clinics network (DLCN) criteria (score ≥ 6), a causative mutation was identified in 116 (64%). Of these, 94 (81%) were detected by genotyping. Ten mutations accounted for more than 50% of the positive cases, with APOB c.10580G>A being the most common. Mutations in LDLR predominated, with (c.2311+1_2312‐1)(2514)del (FH Helsinki) and c.259T>G having the highest frequency. Two novel LDLR mutations were identified. In patients with DLCN score < 6, mutation detection rate was significantly higher at younger age. Conclusion A limited number of mutations explain a major fraction of FH cases in Sweden. Combination of selective genotyping and NGS facilitates the clinical challenge of cost‐effective genetic screening in suspected FH. The frequency of APOB c.10580G>A was higher than previously reported in Sweden. The lack of demonstrable mutations in the LDLR, APOB and PCSK9 genes in ~1/3 of patients with probable FH strongly suggests that additional genetic mechanisms are to be found in phenotypic FH.

show abstract

Improving the yield of genetic testing in familial hypercholesterolaemia

Cited by 6 publications

References 15 publications

Association of Monogenic vs Polygenic Hypercholesterolemia With Risk of Atherosclerotic Cardiovascular Disease

Association of Monogenic vs Polygenic Hypercholesterolemia With Risk of Atherosclerotic Cardiovascular Disease

Machine learning modelling of blood lipid biomarkers in familial hypercholesterolaemia versus polygenic/environmental dyslipidaemia

Founder effects facilitate the use of a genotyping‐based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia

Contact Info

Product

Resources

About