Genetic diagnosis of familial hypercholesterolemia in affected relatives using pedigree tracing

The majority of familial hypercholesterolemia index cases (FH-IC) remain underdiagnosed and undertreated because there are no well-defined strategies for the universal detection of FH. The aim of this study was to evaluate the diagnostic yield of an active screening for FH-IC based on centralized analytical data. From 2016 to 2019, a clinical screening of FH was performed on 469 subjects with severe hypercholesterolemia (low-density lipoprotein cholesterol ≥220 mg/dL), applying the Dutch Lipid Clinic Network (DLCN) criteria. All patients with a DLCN ≥ 6 were genetically tested, as were 10 patients with a DLCN of 3–5 points to compare the diagnostic yield between the two groups. FH was genetically confirmed in 57 of the 84 patients with DLCN ≥ 6, with a genetic diagnosis rate of 67.9% and an overall prevalence of 12.2% (95% confidence interval: 9.3% to 15.5%). Before inclusion in the study, only 36.8% (n = 21) of the patients with the FH mutation had been clinically diagnosed with FH; after genetic screening, FH detection increased 2.3-fold (p < 0.001). The sequential, active screening strategy for FH-IC increases the diagnostic yield for FH with a rational use of the available resources, which may facilitate the implementation of FH universal and family-based cascade screening strategies.

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Lipid profile and genetic status in a familial hypercholesterolemia pediatric population: exploring the LDL/HDL ratio

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2018-1037 ◽

2019 ◽

Vol 57 (7) ◽

pp. 1102-1110 ◽

Cited By ~ 3

Author(s):

Maria Donata Di Taranto ◽

Renato de Falco ◽

Ornella Guardamagna ◽

Giulia Massini ◽

Carola Giacobbe ◽

...

Keyword(s):

Lipid Profile ◽

Familial Hypercholesterolemia ◽

Pediatric Population ◽

Genetic Disorder ◽

Genetic Diagnosis ◽

Density Lipoprotein ◽

Compound Heterozygous ◽

Premature Coronary Artery Disease ◽

Degree Relative ◽

Genetic Status

Abstract Background Familial hypercholesterolemia (FH) is a genetic disorder caused by mutations in genes involved in low-density lipoprotein (LDL) uptake (LDLR, APOB and PCSK9). Genetic diagnosis is particularly useful in asymptomatic children allowing for the detection of definite FH patients. Furthermore, defining their genetic status may be of considerable importance as the compound heterozygous status is much more severe than the heterozygous one. Our study aims at depicting the genetic background of an Italian pediatric population with FH focusing on the correlation between lipid profile and genetic status. Methods Out of 196 patients with clinically suspected FH (LDL-cholesterol [LDL-C] levels above 3.37 mmol/L, cholesterol level above 6.46 mmol/L in a first-degree relative or the presence of premature cardiovascular acute disease in a first/second-degree relative), we screened 164 index cases for mutations in the LDLR, APOB and PCSK9 genes. Results Patients with mutations (129/164) showed increased levels of LDL-C, 95th percentile-adjusted LDL-C and LDL/high-density lipoprotein (HDL) ratio and decreased levels of HDL-C, adjusted HDL-C. The association of the LDL/HDL ratio with the presence of mutations was assessed independently of age, (body mass index) BMI, parental hypercholesterolemia, premature coronary artery disease (CAD), triglycerides by multivariate logistic regression (odds ratio [OR]=1.701 [1.103–2.621], p=0.016). The LDL/HDL ratio gradually increased from patients without mutations to patients with missense mutations, null mutations and compound heterozygotes. Conclusions In conclusion, the LDL/HDL ratio proved to be a better parameter than LDL-C for discriminating patients with from patients without mutations across different genetic statuses.

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Genetics of Hypercholesterolemia: Comparison Between Familial Hypercholesterolemia and Hypercholesterolemia Nonrelated to LDL Receptor

Frontiers in Genetics ◽

10.3389/fgene.2020.554931 ◽

2020 ◽

Vol 11 ◽

Author(s):

Estíbaliz Jarauta ◽

Ana Ma Bea-Sanz ◽

Victoria Marco-Benedi ◽

Itziar Lamiquiz-Moneo

Keyword(s):

Cardiovascular Risk ◽

Familial Hypercholesterolemia ◽

Genetic Defect ◽

Genetic Diagnosis ◽

Ldl Receptor ◽

Lipid Lowering ◽

Atherosclerotic Cardiovascular Disease ◽

Single Nucleotide Variants ◽

Cascade Screening ◽

The Moment

Severe hypercholesterolemia (HC) is defined as an elevation of total cholesterol (TC) due to the increase in LDL cholesterol (LDL-C) >95th percentile or 190 mg/dl. The high values of LDL-C, especially when it is maintained over time, is considered a risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), mostly expressed as ischemic heart disease (IHD). One of the best characterized forms of severe HC, familial hypercholesterolemia (FH), is caused by the presence of a major variant in one gene (LDLR, APOB, PCSK9, or ApoE), with an autosomal codominant pattern of inheritance, causing an extreme elevation of LDL-C and early IHD. Nevertheless, an important proportion of serious HC cases, denominated polygenic hypercholesterolemia (PH), may be attributed to the small additive effect of a number of single nucleotide variants (SNVs), located along the whole genome. The diagnosis, prevalence, and cardiovascular risk associated with PH has not been fully established at the moment. Cascade screening to detect a specific genetic defect is advised in all first- and second-degree relatives of subjects with FH. Conversely, in the rest of cases of HC, it is only advised to screen high values of LDL-C in first-degree relatives since there is not a consensus for the genetic diagnosis of PH. FH is associated with the highest cardiovascular risk, followed by PH and other forms of HC. Early detection and initiation of high-intensity lipid-lowering treatment is proposed in all subjects with severe HC for the primary prevention of ASCVD, with an objective of LDL-C <100 mg/dl or a decrease of at least 50%. A more aggressive reduction in LDL-C is necessary in HC subjects who associate personal history of ASCVD or other cardiovascular risk factors.

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120 Clinical and genetic diagnosis of familial hypercholesterolemia in young subjects in Spain

Atherosclerosis ◽

10.1016/s0021-9150(97)87544-2 ◽

1997 ◽

Vol 130 ◽

pp. S31

Author(s):

J.T. Real ◽

O. Puig ◽

J. Chaves ◽

M. Garcia-Sogo ◽

A. Priego ◽

...

Keyword(s):

Familial Hypercholesterolemia ◽

Genetic Diagnosis ◽

Young Subjects

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The importance of an integrated analysis of clinical, molecular, and functional data for the genetic diagnosis of familial hypercholesterolemia

Genetics in Medicine ◽

10.1038/gim.2015.14 ◽

2015 ◽

Vol 17 (12) ◽

pp. 980-988 ◽

Cited By ~ 17

Author(s):

Asier Benito-Vicente ◽

Ana Catarina Alves ◽

Aitor Etxebarria ◽

Ana Medeiros Medeiros ◽

Cesar Martin ◽

...

Keyword(s):

Familial Hypercholesterolemia ◽

Functional Data ◽

Genetic Diagnosis ◽

Integrated Analysis

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The past, present and future of molecular genetic diagnosis in familial hypercholesterolemia

Clinical Lipidology ◽

10.2217/clp.15.29 ◽

2015 ◽

Vol 10 (5) ◽

pp. 379-385

Author(s):

Ellen RA Thomas

Keyword(s):

Familial Hypercholesterolemia ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

The Past ◽

Molecular Genetic Diagnosis

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PCSK9 Inhibitors in a Statin-Intolerant Transgender Man With Heterozygous Familial Hypercholesterolemia: A Case Report

Journal of the Endocrine Society ◽

10.1210/js.2019-00070 ◽

2019 ◽

Vol 3 (8) ◽

pp. 1461-1464 ◽

Cited By ~ 1

Author(s):

Carlo Pirazzi ◽

Federica Tavaglione ◽

Åsa Tivesten ◽

Stefano Romeo

Keyword(s):

Familial Hypercholesterolemia ◽

Low Density Lipoprotein ◽

Genetic Diagnosis ◽

Density Lipoprotein ◽

Statin Treatment ◽

Lipoprotein Cholesterol ◽

Pcsk9 Inhibitors ◽

Pcsk9 Inhibitor ◽

Lipid Clinic ◽

High Doses

Abstract In female-to-male transgender individuals, testosterone is used to induce masculinization. Sex steroid therapy may increase circulating triglyceride and low-density lipoprotein cholesterol (LDL-C) levels and may decrease high-density lipoprotein cholesterol (HDL-C) levels, resulting in a more atherogenic lipid profile. These potentially adverse effects of androgen therapy may be exacerbated by the presence of familial hypercholesterolemia (FH). We describe the case of a transgender man with genetically diagnosed FH who was intolerant to statins and was started on a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to control his lipoproteins more effectively. The 35-year-old female-to-male transgender individual was referred to our center with a history of elevated LDL-C levels. Despite treatment with high doses of high-potency statins and ezetimibe, he had never achieved a sustained reduction in LDL-C; his levels of LDL-C were fluctuating between 170 and 344 mg/dL (4.4 and 8.9 mmol/L). Moreover, he developed side effects to statins in the form of myalgia and discontinued statin treatment. At the Sahlgrenska Lipid Clinic, a genetic diagnosis of heterozygous FH was established, and PCSK9 inhibitor therapy was started. The patient’s LDL-C level has been reduced by approximately 40% for 23 months, and no adverse events have been reported.

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Abstract 15779: Quality of Life in a Cohort of Familial Hypercholesterolemia Patients Undergoing Molecular Cascade Screening in Brazil

Circulation ◽

10.1161/circ.132.suppl_3.15779 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Ana Cristina Souto ◽

Alexandre Pereira ◽

Cinthia E Jannes ◽

Julia Fukushima ◽

Jose E Krieger ◽

...

Keyword(s):

Quality Of Life ◽

Familial Hypercholesterolemia ◽

Linear Models ◽

Screening Program ◽

Short Form ◽

Smoking Habit ◽

Genetic Diagnosis ◽

Cascade Screening ◽

Social Demographic

Introduction:: Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated disease associated with elevated risk of early cardiovascular disease (CVD) and thus can reduce quality of life. The present health related quality of life (HRQL) investigation, evaluated patients personal interpretation of morbidity burden in daily life. Methods: The study included a total of 1,032 adult individuals participating in a FH molecular cascade-screening program. The involved individuals were index cases (IC n=363), with genetic diagnosis or FH and their first-degree relatives (FDR, n=669). All patients were evaluated at the first session of the molecular diagnosis process. HRQL measurements, mental (MCS) and physical (PCS) component scores, was carried out with the Medical Outcomes Study (MOS) 12-Item Short-Form Health Survey (SF-12) questionnaire. Results: IC were older (52±13.1 vs. 46±16.2 years, P<0.05) and presented lower PCS than FDR (44.7±9.3 vs. 49.2±8.4, P<0.05). No differences were seen on the MCS component. Overall, generalized linear models showed that smoking habit (11.9% prevalence, P=0.006), previous diagnosis of hyperlipidemia (78.6%, P=0.020) and depression (13.5% prevalence, P<0.000) were significant predictors of MCS. The presence of heart failure (6.5%, P=0.018), angina pectoris (12.9%, P=0.005), previous myocardial infarction (12.3%, P=0.012), hypertension (33.9%, P=0.018) and obesity (12.8%, P<0.000) were all predictors of PCS. The presence of arrhythmias (10.7% prevalence) predicted both MCS and PCS (P=0.042 and P=0.00, respectively). Male gender (42.4%, P<0.000) and education level (< 9 years of background, 28% P<0.000) were social-demographic aspects predictive of differences in MCS and PCS, respectively. Conclusions: Reductions in the individuals’ reported quality of life were explained by differences in social-demographic characteristics but mainly by inadequate health/disease status, such as risk factors and previous CVD. Active FH genetic cascade diagnosis by promoting early and adequate medical care and thus preventing early CVD, may improve substantially the subjective appraisal of HRQL.

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