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Familial Hypercholesterolemia: Genetics and Emerging Therapies
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Familial Hypercholesterolemia: Genetics and Emerging Therapies

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 May 2022) | Viewed by 15793

Special Issue Editor

Dr. Mariann Harangi

E-Mail Website
Guest Editor
Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Interests: lipid metabolism; familial hypercholesterolemia; inherited dyslipidemias; atherosclerosis; non-lipid effects of lipid lowering treatment; obesity; diabetes; adipokine; hepatokine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Familial hypercholesterolemia (FH) is an inherited autosomal dominant metabolic disorder characterized by lifelong exposure to highly elevated cholesterol levels, with an estimated prevalence as high as 1 in 200–400 people. Those with FH carry a significantly higher risk of premature coronary artery disease (CAD) compared to the general population. However, early diagnosis and initiation of optimal therapeutic strategies may normalize life expectancy. The most common variants involve mutations of the low-density lipoprotein receptor (LDLR) gene, followed by mutations of the apolipoprotein B-100 (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Previous studies show that FH genetic testing can identify a causal gene variant in 60% to 80% of clinically suspected FH cases. Genetic testing leads to improved FH diagnosis, improved adherence to treatment, improved LDL and total cholesterol levels, accessibility to genetic counseling services and patient education on lifestyle and daily management. On the other hand, potential barriers of FH genetic testing should be identified and eliminated to achieve further clinical benefits associated with FH genetic testing. 

Our aim is to give an overview of the current status of FH genetic testing and its potential future applications, as well as challenges and pitfalls, both from the viewpoint of molecular biologists and clinicians. We would like to highlight the role of genetic testing in early diagnosis, CAD risk stratification and treatment strategies in FH patients and their relatives.

In this Special Issue of Genes, we call for reviews on the current technologies, such as targeted next-generation sequencing, including technical, biological and clinical limitations, current state and the potential clinical utility of genetic testing for FH; as well as original research articles that focus on the discovery of novel genetic variations or mutations that could be used to distinguish clinically relevant disease or predict therapeutic efficacies and outcomes. We look forward to your contributions.

Dr. Mariann Harangi
Guest Editor

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Keywords

  • familial hypercholesterolemia
  • genetics
  • PCSK9 inhibitors
  • low-density lipoprotein
  • homozygous
  • heterozygous

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Published Papers (5 papers)

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Research

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17 pages, 2167 KiB  
Article
Identification of New Genetic Determinants in Pediatric Patients with Familial Hypercholesterolemia Using a Custom NGS Panel
by Lena Rutkowska, Kinga Sałacińska, Dominik Salachna, Paweł Matusik, Iwona Pinkier, Łukasz Kępczyński, Małgorzata Piotrowicz, Ewa Starostecka, Andrzej Lewiński and Agnieszka Gach
Genes 2022, 13(6), 999; https://doi.org/10.3390/genes13060999 - 1 Jun 2022
Cited by 3 | Viewed by 3183
Abstract
The most common form of inherited lipid disorders is familial hypercholesterolemia (FH). It is characterized primarily by high concentrations of the clinical triad of low-density lipoprotein cholesterol, tendon xanthomas and premature CVD. The well-known genetic background are mutations in LDLR, APOB and [...] Read more.
The most common form of inherited lipid disorders is familial hypercholesterolemia (FH). It is characterized primarily by high concentrations of the clinical triad of low-density lipoprotein cholesterol, tendon xanthomas and premature CVD. The well-known genetic background are mutations in LDLR, APOB and PCSK9 gene. Causative mutations can be found in 60–80% of definite FH patients and 20–30% of those with possible FH. Their occurrence could be attributed to the activity of minor candidate genes, whose causal mechanism has not been fully discovered. The aim of the conducted study was to identify disease-causing mutations in FH-related and candidate genes in pediatric patients from Poland using next generation sequencing (NGS). An NGS custom panel was designed to cover 21 causative and candidate genes linked to primary dyslipidemia. Recruitment was performed using Simon Broome diagnostic criteria. Targeted next generation sequencing was performed on a MiniSeq sequencer (Illumina, San Diego, CA, USA) using a 2 × 150 bp paired-end read module. Sequencing data analysis revealed pathogenic and possibly pathogenic variants in 33 out of 57 studied children. The affected genes were LDLR, APOB, ABCG5 and LPL. A novel pathogenic 7bp frameshift deletion c.373_379delCAGTTCG in the exon 4 of the LDLR gene was found. Our findings are the first to identify the c.373_379delCAGTTCG mutation in the LDLR gene. Furthermore, the double heterozygous carrier of frameshift insertion c.2416dupG in the LDLR gene and missense variant c.10708C>T in the APOB gene was identified. The c.2416dupG variant was defined as pathogenic, as confirmed by its cosegregation with hypercholesterolemia in the proband’s family. Although the APOB c.10708C>T variant was previously detected in hypercholesterolemic patients, our data seem to demonstrate no clinical impact. Two missense variants in the LPL gene associated with elevated triglyceride plasma level (c.106G>A and c.953A>G) were also identified. The custom NGS panel proved to be an effective research tool for identifying new causative aberrations in a genetically heterogeneous disease as familial hypercholesterolemia (FH). Our findings expand the spectrum of variants associated with the FH loci and will be of value in genetic counseling among patients with the disease. Full article
(This article belongs to the Special Issue Familial Hypercholesterolemia: Genetics and Emerging Therapies)
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13 pages, 1432 KiB  
Article
Establishing the Mutational Spectrum of Hungarian Patients with Familial Hypercholesterolemia
by László Madar, Lilla Juhász, Zsuzsanna Szűcs, Lóránt Kerkovits, Mariann Harangi and István Balogh
Genes 2022, 13(1), 153; https://doi.org/10.3390/genes13010153 - 15 Jan 2022
Cited by 4 | Viewed by 2781
Abstract
Familial hypercholesterolemia (FH) is one of the most common autosomal, dominantly inherited diseases affecting cholesterol metabolism, which, in the absence of treatment, leads to the development of cardiovascular complications. The disease is still underdiagnosed, even though an early diagnosis would be of great [...] Read more.
Familial hypercholesterolemia (FH) is one of the most common autosomal, dominantly inherited diseases affecting cholesterol metabolism, which, in the absence of treatment, leads to the development of cardiovascular complications. The disease is still underdiagnosed, even though an early diagnosis would be of great importance for the patient to receive proper treatment and to prevent further complications. No studies are available describing the genetic background of Hungarian FH patients. In this work, we present the clinical and molecular data of 44 unrelated individuals with suspected FH. Sequencing of five FH-causing genes (LDLR, APOB, PCSK9, LDLRAP1 and STAP1) has been performed by next-generation sequencing (NGS). In cases where a copy number variation (CNV) has been detected by NGS, confirmation by multiplex ligation-dependent probe amplification (MLPA) has also been performed. We identified 47 causal or potentially causal (including variants of uncertain significance) LDLR and APOB variants in 44 index patients. The most common variant in the APOB gene was the c.10580G>A p.(Arg3527Gln) missense alteration, this being in accordance with literature data. Several missense variants in the LDLR gene were detected in more than one index patient. LDLR variants in the Hungarian population largely overlap with variants detected in neighboring countries. Full article
(This article belongs to the Special Issue Familial Hypercholesterolemia: Genetics and Emerging Therapies)
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14 pages, 691 KiB  
Article
Multiplex Protein Biomarker Profiling in Patients with Familial Hypercholesterolemia
by Dana Dlouha, Milan Blaha, Eva Rohlova, Jaroslav A. Hubacek, Vera Lanska, Jakub Visek and Vladimir Blaha
Genes 2021, 12(10), 1599; https://doi.org/10.3390/genes12101599 - 12 Oct 2021
Cited by 3 | Viewed by 2390
Abstract
Familial hypercholesterolemia (FH), is an autosomal dominant disorder caused by mutations in the LDLR, APOB, PCSK9, and APOE genes and is characterized by high plasma levels of total and low-density lipoprotein (LDL) cholesterol. Our study aimed to analyze the influences [...] Read more.
Familial hypercholesterolemia (FH), is an autosomal dominant disorder caused by mutations in the LDLR, APOB, PCSK9, and APOE genes and is characterized by high plasma levels of total and low-density lipoprotein (LDL) cholesterol. Our study aimed to analyze the influences of two different therapies on a wide spectrum of plasma protein biomarkers of cardiovascular diseases. Plasma from FH patients under hypolipidemic therapy (N = 18; men = 8, age 55.4 ± 13.1 years) and patients under combined long-term LDL apheresis/hypolipidemic therapy (N = 14; men = 7; age 58.0 ± 13.6 years) were analyzed in our study. We measured a profile of 184 cardiovascular disease (CVD) associated proteins using a proximity extension assay (PEA). Hypolipidemic therapy significantly (all p < 0.01) influenced 10 plasma proteins (TM, DKK1, CCL3, CD4, PDGF subunit B, AGRP, IL18, THPO, and LOX1 decreased; ST2 increased). Under combined apheresis/hypolipidemic treatment, 18 plasma proteins (LDLR, PCSK9, MMP-3, GDF2, CTRC, SORT1, VEGFD, IL27, CCL24, and KIM1 decreased; OPN, COL1A1, KLK6, IL4RA, PLC, TNFR1, GLO1, and PTX3 increased) were significantly affected (all p < 0.006). Hypolipidemic treatment mainly affected biomarkers involved in vascular endothelial maintenance. Combined therapy influenced proteins that participate in cholesterol metabolism and inflammation. Full article
(This article belongs to the Special Issue Familial Hypercholesterolemia: Genetics and Emerging Therapies)
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Review

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19 pages, 971 KiB  
Review
Clinical Aspects of Genetic and Non-Genetic Cardiovascular Risk Factors in Familial Hypercholesterolemia
by Eszter Berta, Noémi Zsíros, Miklós Bodor, István Balogh, Hajnalka Lőrincz, György Paragh and Mariann Harangi
Genes 2022, 13(7), 1158; https://doi.org/10.3390/genes13071158 - 27 Jun 2022
Cited by 7 | Viewed by 3573
Abstract
Familial hypercholesterolemia (FH) is the most common monogenic metabolic disorder characterized by considerably elevated low-density lipoprotein cholesterol (LDL-C) levels leading to enhanced atherogenesis, early cardiovascular disease (CVD), and premature death. However, the wide phenotypic heterogeneity in FH makes the cardiovascular risk prediction challenging [...] Read more.
Familial hypercholesterolemia (FH) is the most common monogenic metabolic disorder characterized by considerably elevated low-density lipoprotein cholesterol (LDL-C) levels leading to enhanced atherogenesis, early cardiovascular disease (CVD), and premature death. However, the wide phenotypic heterogeneity in FH makes the cardiovascular risk prediction challenging in clinical practice to determine optimal therapeutic strategy. Beyond the lifetime LDL-C vascular accumulation, other genetic and non-genetic risk factors might exacerbate CVD development. Besides the most frequent variants of three genes (LDL-R, APOB, and PCSK9) in some proband variants of other genes implicated in lipid metabolism and atherogenesis are responsible for FH phenotype. Furthermore, non-genetic factors, including traditional cardiovascular risk factors, metabolic and endocrine disorders might also worsen risk profile. Although some were extensively studied previously, others, such as common endocrine disorders including thyroid disorders or polycystic ovary syndrome are not widely evaluated in FH. In this review, we summarize the most important genetic and non-genetic factors that might affect the risk prediction and therapeutic strategy in FH through the eyes of clinicians focusing on disorders that might not be in the center of FH research. The review highlights the complexity of FH care and the need of an interdisciplinary attitude to find the best therapeutic approach in FH patients. Full article
(This article belongs to the Special Issue Familial Hypercholesterolemia: Genetics and Emerging Therapies)
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Other

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10 pages, 840 KiB  
Case Report
A Clinical Case of a Homozygous Deletion in the APOA5 Gene with Severe Hypertriglyceridemia
by Petr Andreevich Vasiluev, Olga N. Ivanova, Natalia A. Semenova, Tatiana V. Strokova, Natalia N. Taran, Uliana V. Chubykina, Marat V. Ezhov, Ekaterina Y. Zakharova, Elena L. Dadli and Sergey I. Kutsev
Genes 2022, 13(6), 1062; https://doi.org/10.3390/genes13061062 - 14 Jun 2022
Cited by 4 | Viewed by 2406
Abstract
Background: Hypertriglyceridemia (HTG) is one of the most common forms of lipid metabolism disorders. The leading clinical manifestations are pancreatitis, atherosclerotic vascular lesions, and the formation of eruptive xanthomas. The most severe type of HTG is primary (or hereditary) hypertriglyceridemia, linked to pathogenic [...] Read more.
Background: Hypertriglyceridemia (HTG) is one of the most common forms of lipid metabolism disorders. The leading clinical manifestations are pancreatitis, atherosclerotic vascular lesions, and the formation of eruptive xanthomas. The most severe type of HTG is primary (or hereditary) hypertriglyceridemia, linked to pathogenic genetic variants in LPL, APOC2, LMF1, and APOA5 genes. Case: We present a clinical case of severe primary hypertriglyceridemia (TG level > 55 mmol/L in a 4-year-old boy) in a consanguineous family. The disease developed due to a previously undescribed homozygous deletion in the APOA5 gene (NM_052968: c.579_592delATACGCCGAGAGCC p.Tyr194Gly*68). We also evaluate the clinical significance of a genetic variant in the LPL gene (NM_000237.2: c.106G>A (rs1801177) p.Asp36Asn), which was previously described as a polymorphism. In one family, we also present a different clinical significance even in heterozygous carriers: from hypertriglyceridemia to normotriglyceridemia. We provide evidence that this heterogeneity has developed due to polymorphism in the LPL gene, which plays the role of an additional trigger. Conclusions: The homozygous deletion of the APOA5 gene is responsible for the severe hypertriglyceridemia, and another SNP in the LPL gene worsens the course of the disease. Full article
(This article belongs to the Special Issue Familial Hypercholesterolemia: Genetics and Emerging Therapies)
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