Publications by authors named "Defesche J"
Article Synopsis
- Familial hypercholesterolemia (FH) is a genetic disorder characterized by high LDL cholesterol levels and a greater risk of early heart disease, and traditional methods of classifying LDL receptor gene (LDLR) variants might overlook individual differences in cholesterol levels and CAD risk.
- The study screened participants for LDLR variants and calculated age- and sex-adjusted LDL cholesterol percentiles for variant carriers, then grouped them into strata to evaluate coronary artery disease (CAD) risk.
- Results showed that LDLR variant carriers had a significantly higher CAD risk than non-carriers, with the risk varying depending on cholesterol levels and the type of LDLR variant, indicating that the new classification method could improve risk assessment for FH patients.
Background: Familial hypercholesterolemia (FH) is a common but underdiagnosed genetic disorder characterized by high low-density lipoprotein cholesterol levels and premature cardiovascular disease. Current sequencing methods to diagnose FH are expensive and time-consuming. In this study, we evaluated the accuracy of a low-cost, high-throughput genotyping array for diagnosing FH.
View Article and Find Full Text PDFBackground: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease (CVD). Both the heterozygous form and the very severe homozygous form can be diagnosed by genetic testing and by clinical criteria. Genetic testing can discern FH in a form caused by complete absence of the LDL-receptors, the negative variant and a form leading to reduced activity of the LDL receptors, the defective variant.
View Article and Find Full Text PDFArticle Synopsis
- Homozygous familial hypercholesterolemia (HoFH) is a serious genetic disorder that leads to very high cholesterol levels, significantly increasing health risks.
- Couples who both have heterozygous familial hypercholesterolemia have a 25% chance of having a child with HoFH, prompting the need for informed reproductive decisions.
- This study highlights the importance of counseling from healthcare specialists, showing that one couple chose prenatal testing with a possible termination option, while another accepted the risk without testing, underlining the need for thorough preconception counseling.
Article Synopsis
- Lipoprotein(a) [Lp(a)] levels are mainly determined by genetics, and their impact on patients with familial hypercholesterolemia (FH) undergoing genetic testing is not well understood.
- A study analyzed 1504 patients using specific genetic markers to estimate Lp(a) levels, which helped reclassify their LDL-cholesterol levels and assess their cardiovascular risk.
- The findings revealed that considering Lp(a) reclassified a significant number of patients' FH diagnosis and ASCVD risk, highlighting the need for clear guidelines to avoid missing FH variants during genetic testing.
Article Synopsis
- - Familial Dysbetalipoproteinemia (FD) is a common genetic condition that significantly increases the risk of cardiovascular disease due to high levels of certain cholesterol types, typically caused by genetic variants in the APOE gene.
- - Diagnosing FD involves confirming both the genetic variant and related symptoms, with Next Generation Sequencing helping identify potentially pathogenic APOE gene variants.
- - The article discusses two methods to determine if a new APOE variant causes FD: a comprehensive approach involving various tests and a more practical one for patient management in clinical settings.
Background: Inclisiran is a small interfering RNA molecule that reduces low-density lipoprotein cholesterol (LDL-C) by inhibition of proprotein convertase subtilisin/kexin type 9. This subcutaneous, twice-yearly administered agent has been shown to effectively and safely lower LDL-C in adult patients with established atherosclerotic cardiovascular disease, adults at high risk for atherosclerotic cardiovascular disease, as well as in adults with heterozygous familial hypercholesterolaemia. With the current, limited treatment options available to reach treatment goals in children with severe heterozygous familial hypercholesterolaemia, homozygous familial hypercholesterolaemia, or statin intolerance, inclisiran could be a valuable new therapeutic option.
View Article and Find Full Text PDFBackground And Aims: Low-density lipoprotein cholesterol (LDL-C) levels vary in patients with familial hypercholesterolemia (FH) and can be explained by a single deleterious genetic variant or by the aggregate effect of multiple, common small-effect variants that can be captured in a polygenic score (PS). We set out to investigate the contribution of a previously published PS to the inter-individual LDL-C variation and coronary artery disease (CAD) risk in patients with a clinical FH phenotype.
Methods: First, in a cohort of 628 patients referred for genetic FH testing, we evaluated the distribution of a PS for LDL-C comprising 12 genetic variants.
Article Synopsis
- The Dutch genetic screening program for familial hypercholesterolemia (FH), active from 1994 to 2014, identified over 1500 cases per year and laid the groundwork for improved diagnostic tools and treatments despite government funding cuts.
- After 2014, the community and insurance companies collaborated to continue the program, broadening the screening to include other heritable dyslipidemias and developing a comprehensive next-generation sequencing (NGS) panel.
- The NGS panel not only identifies more patients at risk for cardiovascular diseases but also enhances understanding of genetic dyslipidemias, revealing complex genetic mechanisms and facilitating personalized treatments.
Article Synopsis
- * Researchers sequenced genes involved in lipid metabolism in patients with high cholesterol, finding that 14.9% had pathogenic variants; this included mostly LDLR variants, with a notable decrease in detection rates over the years, particularly among younger patients.
- * The study suggests that enhanced clinical criteria and algorithms are necessary to better identify patients with familial hypercholesterolemia, as minor gene variants may also contribute to the condition's phenotype.
Beyond the Usual Suspects: Expanding on Mutations and Detection for Familial Hypercholesterolemia.
Expert Rev Mol Diagn
September 2021
Article Synopsis
- * Advances in genetic technologies, especially next-generation sequencing, have improved the understanding of FH by identifying variants and exploring their relationship to the condition, leading to better diagnosis and treatment options.
- * The demand for genetic testing for FH is increasing as costs decrease and new treatments necessitate genetic verification, highlighting the need for training healthcare professionals in these molecular technologies for effective patient care.
Background And Aims: Familial hypercholesterolemia (FH) is caused by pathogenic variants in LDLR, APOB, or PCSK9 genes (designated FH+). However, a significant number of clinical FH patients do not carry these variants (designated FH-). Here, we investigated whether variants in intronic regions of LDLR attribute to FH by affecting pre-mRNA splicing.
View Article and Find Full Text PDFObjective: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor () mutations account for >90% of cases, apolipoprotein B () mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 () gain of function mutations are rare (<1% of cases). We aimed to evaluate the functional impact of several novel variants in a cohort of patients with FH by genetic cascade screening and in vitro functionality assays.
View Article and Find Full Text PDFArticle Synopsis
- Familial hypercholesterolemia (FH) is a genetic disorder identified by high levels of LDL cholesterol, but genetic variants are missing in 12-60% of patients, prompting this study to explore DNA methylation as a potential factor in those FH mutation-negative patients.
- The study involved 78 FH mutation-negative and 58 mutation-positive male patients, using DNA methylation profiling and statistical analyses to compare genetic differences related to lipid metabolism.
- Findings indicated a specific hypomethylated site in the CPT1A gene for mutation-negative patients and successful differentiation between the two groups using machine learning, pointing to potential methylation changes outside traditional lipid genes.*
Background: Familial hypercholesterolemia is characterised by high low-density lipoprotein-cholesterol levels and is caused by a pathogenic variant in , or . We investigated which proportion of suspected familial hypercholesterolemia patients was genetically confirmed, and whether this has changed over the past 20 years in The Netherlands.
Methods: Targeted next-generation sequencing of 27 genes involved in lipid metabolism was performed in patients with low-density lipoprotein-cholesterol levels greater than 5 mmol/L who were referred to our centre between May 2016 and July 2018.
Background: Familial hypercholesterolemia (FH) is a common inherited disease characterized by elevated low-density lipoprotein cholesterol (LDL-C) plasma levels and increased cardiovascular disease risk. Most patients carry a mutation in the low-density lipoprotein receptor gene (LDLR). Common and rare variants in the genes encoding adenosine triphosphate-binding cassette transporters G5 and G8 (ABCG5 and ABCG8) have been shown to affect LDL-C levels.
View Article and Find Full Text PDFReducing the Clinical and Public Health Burden of Familial Hypercholesterolemia: A Global Call to Action.
JAMA Cardiol
February 2020
Article Synopsis
- - Familial hypercholesterolemia (FH) is a genetic condition affecting 1 in 200 to 250 people globally, causing severe health risks due to lack of diagnosis and treatment, with only 10% of cases being identified.
- - The World Health Organization designated FH as a public health priority in 1998 and issued 11 recommendations to improve its diagnosis, treatment, and awareness, but there has been minimal progress in their implementation over the last two decades.
- - In 2018, the FH Foundation and World Heart Federation held meetings to update these recommendations by gathering input from international stakeholders across various income regions to address gaps and enhance FH management.
Article Synopsis
- Homozygous familial hypercholesterolemia (hoFH) is typically diagnosed through specific genetic markers or significantly high LDL-C levels, which are often not well understood in children.
- The study aimed to analyze a pediatric group with proven familial hypercholesterolemia (FH) and determine how many heterozygous patients might actually have a second mutation qualifying them for hoFH.
- Results indicated that a significant number of pediatric hoFH patients did not meet the standard LDL-C criteria, leading to the suggestion that current diagnostic thresholds for hoFH in children need reevaluation.
A Deep Intronic Variant in LDLR in Familial Hypercholesterolemia.
Circ Genom Precis Med
December 2018
Article Synopsis
- Familial hypercholesterolemia (FH) is a genetic disorder leading to high LDL cholesterol levels, typically caused by mutations in specific genes; however, this study identifies a novel intronic mutation in LDLR in a family where common mutations were not found.
- Whole genome sequencing was performed on both affected and unaffected family members to trace the genetic cause of FH, revealing a mutation that disrupts splicing and results in a defective LDLR protein.
- The identified mutation, c.2140+103G>T, was shown to be linked to the FH phenotype in multiple family generations, highlighting the importance of examining non-coding regions of related genes for unexplained FH cases.
Article Synopsis
- * It uses familial hypercholesterolemia (FH) as a case study, highlighting the need for identifying causative variants to enhance treatment and support family screenings.
- * The Clinical Genome Resource and the FH Variant Curation Expert Panel are working to increase the submission of variants to ClinVar while identifying areas for improvement in data submission to enhance variant interpretation for FH patients.
Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing.
View Article and Find Full Text PDFArticle Synopsis
- Mutations in genes related to cholesterol metabolism are linked to familial hypercholesterolemia (FH), which can be heterozygous or homozygous.
- The study aimed to assess how different types of genetic mutations impact the cholesterol-lowering effects of alirocumab, a medication used to treat high cholesterol.
- Results showed that patients with double heterozygous, compound heterozygous, or homozygous mutations experienced significant reductions in LDL cholesterol levels with alirocumab, demonstrating its effectiveness across these genetic variations.
Article Synopsis
- - Familial hypercholesterolaemia is an inherited condition causing high levels of LDL cholesterol from birth, which can increase the risk of cardiovascular disease over time.
- - The primary cause is often mutations in the LDLR gene, but other genes like APOB and PCSK9 can also contribute; diagnosis typically involves elevated LDL cholesterol levels and family history.
- - Treatment with cholesterol-lowering medications, especially statins, is crucial for improving health outcomes and longevity, and may need to be complemented with other therapies as necessary.