Familial Hypercholesterolemia Cases Research Articles

Variants in LPA are associated with Familial Hypercholesterolaemia: whole genome sequencing analysis in the 100,000 Genomes Project

Abstract Background Familial Hypercholesterolaemia (FH) is an inherited disease of high LDL-cholesterol (LDL-C) caused by defects in LDLR, APOB, APOE and PCSK9 genes. A pathogenic variant cannot be found in ∼60% of clinical FH patients. Using whole genome sequencing (WGS) we examined genetic determinants of FH. Methods WGS data generated by the 100,000 Genomes Project (100KGP) included 536 FH patients diagnosed using the FH Simon Broome criteria. Rare variants in known FH genes were analysed. Genome-wide association study (GWAS) between 443 FH variant-negative unrelated FH cases and 77,275 control participants of the 100KGP was run using high coverage WGS data. Polygenic risk scores for LDL-C (LDL PRS) and lipoprotein(a) (Lp(a) PRS) were computed. Results An FH-causing variant was found in 17.4% of FH cases. GWAS identified the LPA gene locus being significantly associated (p<1x10-8). FH variant-negative participants had higher LDL and Lp(a) PRSs in comparison to the controls (p<1.0×10-16 and p<4.09×10-6, respectively). Similar associations were found in the monogenic FH with both LDL and Lp(a) PRSs being higher than in controls (p<4.03×10-4 and p<3.01x10-3, respectively). High LDL PRS was observed in 36.4% of FH variant-negative cases, whereas high Lp(a) PRS in 18.5%, with 7.0% having both high LDL and Lp(a) PRSs. Conclusions This genome-wide analysis of monogenic and polygenic FH causes confirms a complex and heterogenous architecture of hypercholesterolaemia, with the LPA gene playing a significant role. Both Lp(a) and LDL-C should be measured for precision FH diagnosis. Specific therapies to lower Lp(a) should be targeted to those who will benefit most.

Case detection of familial hypercholesterolemia using various criteria during an annual health examination in the workplace

BackgroundEarly diagnosis and appropriate treatment of subjects with familial hypercholesterolemia (FH) could prevent cardiovascular disease (CAD). ObjectiveWe aimed to identify potential cases of FH during a workplace screening and to explore their clinical data. MethodPersonnel who attended an annual health examination were invited to answer a questionnaire and to provide consent to review their laboratory results. FH was clinically diagnosed using any one of the three standard criteria: Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), and Make Early Diagnosis to Prevent Early Deaths (MEDPED). Clinical characteristics were compared between FH and unlikely FH subjects. ResultsAmong 6607 participants, potential cases of FH were identified in 2.5 % by DLCN, 4.0 % by SB, and 0.8 % by MEDPED alone. Premature CAD, hypertension, and current smoking were significantly more common in potential FH subjects than in unlikely FH subjects. Potential FH subjects also had significantly higher body mass index, waist circumference, blood pressure, fasting plasma glucose and triglyceride levels than unlikely FH subjects. Among potential FH subjects, lipid-lowering medication was used in 28.4 %. The achievement of the LDL-C goal (<100 mg/dL) in potential FH subjects was significantly lower than that in unlikely FH subjects (15 % vs. 28 %, respectively, P = 0.005) despite a higher rate of high-intensity statin use (25 % vs. 10 %, respectively, P = 0.002). ConclusionThe workplace screening of FH detected a significant number of potential FH subjects with higher cardiovascular risk. This strategy identified individuals for whom intensification of both lifestyle modifications and pharmacological treatment should be a priority.

The effectiveness and barrier of reverse cascade screening for paediatric familial hypercholesterolaemia

Abstract Background Familial Hypercholesterolaemia (FH) is an autosomal dominant genetic disorder that is prevalent in one out of every 300 individuals in the general population. Recognized as an actionable condition, early diagnosis of FH in children is crucial to prevent the onset of atherosclerosis, and equally important is the identification of parents before the development of coronary artery disease events. Therefore, the significance of universal FH screening during childhood combined with reverse cascade screening has been increasingly acknowledged. To achieve these objectives, in our region, universal lipid screening is conducted in elementary schools for children aged 9 or 10 years, annually screening approximately 8,000 individuals, with those identified being referred through a three-step process to four major healthcare facilities within the prefecture. However, the effectiveness of reverse-cascade screening remains unclear. Purpose Our study aimed to assess the effectiveness of and identify barriers to implementing reverse cascade screening in conjunction with universal lipid screening. Methods We conducted a single-center, retrospective observational study from January 2018 to July 2023 and evaluated the utility of reverse cascade screening for children genetically diagnosed with FH following universal screening. This study analysed prevalent barriers and identified families with suspected FH through reverse cascade screening, counting those with Potential FH among second-degree relatives. Beyond successful identification, we categorized the frequently encountered barriers into five distinct categories: bereavement, prior cardiovascular events, dyslipidaemia with unspecified LDL-C levels, incomplete family history information, and inadequate disease awareness of FH. Reverse FH diagnosis adhered to current guidelines. Results and Discussion Of 151 paediatric patients referred to our facility, 67 were genotypically confirmed to have FH. Excluding 8 cases of divorce and 4 cases of tracking challenges, 55 patients were finally analysed. 62 patients were diagnosed with reverse FH, and appropriate treatment was initiated. Notably, 158 cases of Potential FH were identified. (25 first-degree and 133 second-degree relatives). While a higher number of reverse FH diagnoses were observed in first-degree relatives (55 cases), the diagnostic yield was lower among second-degree relatives (seven cases). Common barriers for second-degree relatives included dyslipidaemia with unspecified LDL-C levels (42 cases) and incomplete family history information (66 cases). Conclusion Integrating universal screening with reverse cascade screening facilitates the identification of new FH cases. A comprehensive strategy for diagnosing reverse FH is paramount, raising disease awareness, genetic testing, the development of a family-based care plan, and enhancing access to information and communication technologies.

Familial hypercholesterolaemia with high triglycerides: A diagnostic challenge.

Combined or mixed hyperlipidaemia is characterised by hypercholesterolaemia together with high triglyceride concentrations. It is found in approximately 1 in 100 people in the United Kingdom. Most cases are secondary to an underlying condition such as the metabolic syndrome, diabetes mellitus (especially poorly controlled) or individuals with a high alcohol intake. Mixed hyperlipidaemia is also a feature of some primary hyperlipidaemia conditions such familial combined hyperlipidaemia (FCH) or type III hyperlipidaemia (dysbetalipoproteinaemia). One differential diagnosis for mixed hyperlipidaemia that can easily be overlooked is a patient with an underlying diagnosis of familial hypercholesterolaemia (FH) who also has a hypertriglyceridaemia due to any other cause. Those patients may have very high total and low-density lipoprotein cholesterol concentrations (LDL-C) with a moderately elevated triglyceride concentration. In this article, we report 4 cases of familial hypercholesterolaemia, confirmed by genetic testing, in patients initially presenting with hypertriglyceridaemia in addition to high total cholesterol and LDL-C. This article discusses the diagnostic challenges associated with this presentation and highlights the key role of directly measuring LDL-C to aid diagnosis in these specific situations.

Review of p.(Val429Met), a Variant of LDLR That Is Associated with Familial Hypercholesterolemia

Patients affected by familial hypercholesterolemia possess elevated low-density lipoprotein cholesterol and therefore have greater risk for cardiovascular disease. About 90% of familial hypercholesterolemia cases are associated with aberrant LDLR. Over 3500 LDLR variants have been identified, 15% of which are considered “pathogenic.” Given the genetic diversity of LDLR variants, specific variants rarely receive attention. However, investigators have proposed the critical evaluation of individual variants as a method to clarify knowledge and to resolve discrepancies in the literature. This article reviews p.(Val429Met) (rs28942078) in the areas of pathology, epidemiology, lipid-lowering therapy, and genetic testing. The p.(Val429Met) variant is associated with a missense point substitution in exon 9 of chromosome 19. Biochemical studies have found severely reduced low-density lipoprotein receptor protein in autologous and heterologous expression systems. Additionally, there are inconsistencies regarding the functional classification of p.(Val429Met). Considered to be of European origin, p.(Val429Met) is found in extant populations due to founder effects. Evidence from clinical trials have also demonstrated variable responses to newer lipid-lowering therapies in patients with a p.(Val429Met) variant. Proper clinical detection and adequate genetic testing have been shown to greatly improve outcomes. Future research may be aimed at resolving discrepancies to better comprehend the implications of familial hypercholesterolemia.

TARGETED SEQUENCING REVEAL TWO PATHOGENIC MUTATIONS IN LDLR AND APOE GENES IN PATIENT WITH FAMILY HYPERCHOLESTEROLEMIA: CASE REPORT

Familial hypercholesterolemia (FH) is a serious inherited disorder that can lead to early development of cardiovascular disease (CVD) due to the high blood cholesterol levels. In our study, we identified in FH patient likely pathogenic variant of LDLR and APOE genes. Interest in the homozygous state of FH is understandable given its rarity and severe health consequences. The homozygous state, when both LDL receptor alleles mutated, demonstrates even higher cholesterol levels and an earlier and more severe clinical course compared with the heterozygous state. In our study, we report an interesting case of homozygous FH due to its rare prevalence. Patient U., 16 years old, woman, admitted to the National Research Cardiac Surgery Center (NRCC), was diagnosed with FH, congenital heart disease (CHD), bicuspidal aortic valve (AV) type 1. Both parents (mother and father) were included for reliable analysis. DNA was isolated from the venous blood sample by using the column method of QIAamp DNA Mini Kit. Targeted NGS using TruSight Cardio panel for 174 genes was performed on MiSeq, Illumina. Identified genetic variants were classified according to the ACMG guidelines. Pathogenic variants were validated by Sanger sequencing. Additionally, databases of the VarSome and ClinVar were used for analysis. Sequencing of 96 genes and bioinformatics analysis identified 2 likely pathogenic variants - C526T:p.R176C in APOE and G295A:p.E99K in LDLR gene, 4 uncertain significance variants in APOB, TTN, COL3A1, NOTCH1 and 90 benign variants in APOB, TTN, LAMA4, MYPN, DMD. LDLR (G295A:p.E99K) and APOE (C526T:p.R176C) were validated and confirmed by Sanger sequencing in patients and her father and mother. The main function of the APOE gene is to make the protein apolipoprotein E, which is involved in fat metabolism. In our study, the patient had a heterozygous variant of СT polymorphism rs7412 in the APOE gene, which indicates the presence of a possible disorder of fat metabolism. LDLR gene encodes a protein called low-density lipoprotein receptor, which is responsible for the uptake of cholesterol-carrying lipoprotein particles in cells. In our study, a patient with a homozygous AA variant of the LDLR gene was found to be pathogenic. Disruption of the uptake of cholesterol-carrying lipoprotein particles in cells can have serious consequences for the body. This can lead to cholesterol accumulation in the blood and tissues, which in turn can contribute to the development of atherosclerosis and other CVD. We found that both parents had a heterozygous genotype of G295A:p.E99K in LDLR gene; and mother had a heterozygous genotype and father had a homozygous genotype of C526T:p.R176C in APOE gene. In our study, we found the genetic mutations - two likely pathogenic genetic variants LDLR (G295A:p.E99K) and APOE (C526T:p.R176C) associated with FH in patient with clinical phenotype of FH using TruSight Cardio targeted panel of 96 genes. Genetic testing using targeted NGS or whole exome sequencing would be useful for right diagnosis and might improve personalize treatment for these patients. To identify other genes associated with FH whole exome sequencing can be recommend. Supported by Committee of Science of the Ministry of Science and Higher Education of Republic of Kazakhstan (AP14869903), (BR21881970) and Nazarbayev University CRP (211123CRP1608).

Cardiovascular risk is more important in index cases of familial hypercholesterolemia

Cardiovascular risk is more important in index cases of familial hypercholesterolemia

"I don't think people should die young": perspectives of parents with children diagnosed with familial hypercholesterolemia.

Familial Hypercholesterolemia (FH) is an inherited disorder that significantly increases an individual's risk of developing premature cardiovascular disease (CVD). Early intervention involving lifestyle modification and medication is crucial in preventing CVD. Prior studies have shown that lipid-lowering therapy in children is safe and effective. Despite FH being a treatable and manageable condition, the condition is still underdiagnosed and undertreated. Universal lipid screening (ULS) in children has been recommended by some medical experts in the United States as a strategy to identify cases of FH and maximize the benefits of early invention. However, lipid screening is not routinely offered in pediatric clinics. This study aimed to explore parental experience with FH diagnosis in their children, identify key facilitators and barriers in children's diagnosis and care, and examine parental perspectives on ULS in children in the United States. A total of fourteen semi-structured interviews were conducted with participants recruited through the Family Heart Foundation. Thematic analysis identified three key themes: role of family history in facilitating child's FH diagnosis, barriers and challenges in post-diagnosis care, and attitudes towards ULS in children. All participants supported ULS in children and emphasized the value of early diagnosis and treatment for FH. However, a lack of guidance or referral after the child's diagnosis was a concern raised by many participants. This underscores the need for accessible and comprehensive care amid ongoing efforts to increase pediatric diagnosis of FH.

Cellular and functional evaluation of LDLR missense variants reported in hypercholesterolemic patients demonstrates their hypomorphic impacts on trafficking and LDL internalization.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by increased LDL-cholesterol levels. About 85% of FH cases are caused by LDLR mutations encoding the low-density lipoprotein receptor (LDLR). LDLR is synthesized in the endoplasmic reticulum (ER) where it undergoes post-translational modifications and then transported through Golgi apparatus to the plasma membrane. Over 2900 LDLR variants have been reported in FH patients with limited information on the pathogenicity and functionality of many of them. This study aims to elucidate the cellular trafficking and functional implications of LDLR missense variants identified in suspected FH patients using biochemical and functional methods. We used HeLa, HEK293T, and LDLR-deficient-CHO-ldlA7 cells to evaluate the subcellular localization and LDL internalization of ten LDLR missense variants (p.C167F, p.D178N, p.C243Y, p.E277K, p.G314R, p.H327Y, p.D477N, p.D622G, p.R744Q, and p.R814Q) reported in multiethnic suspected FH patients. We also analyzed the functional impact of three variants (p.D445E, p.D482H, and p.C677F), two of which previously shown to be retained in the ER. We show that p.D622G, p.D482H, and p.C667F are largely retained in the ER whereas p.R744Q is partially retained. The other variants were predominantly localized to the plasma membrane. LDL internalization assays in CHO-ldlA7 cells indicate that p.D482H, p.C243Y, p.D622G, and p.C667F have quantitatively lost their ability to internalize Dil-LDL with the others (p.C167F, p.D178N, p.G314R, p.H327Y, p.D445E, p.D477N, p.R744Q and p.R814Q) showing significant losses except for p.E277K which retained full activity. However, the LDL internalization assay is only to able evaluate the impact of the variants on LDL internalization and not the exact functional defects such as failure to bind LDL. The data represented illustrate the hypomorphism nature of variants causing FH which may explain some of the variable expressivity of FH. Our combinatorial approach of in silico, cellular, and functional analysis is a powerful strategy to determine pathogenicity and FH disease mechanisms which may provide opportunitites for novel therapeutic strategies.

Improving the Detection of Potential Cases of Familial Hypercholesterolemia: Could Machine Learning Be Part of the Solution?

Familial hypercholesterolemia (FH), while highly prevalent, is a significantly underdiagnosed monogenic disorder. Improved detection could reduce the large number of cardiovascular events attributable to poor case finding. We aimed to assess whether machine learning algorithms outperform clinical diagnostic criteria (signs, history, and biomarkers) and the recommended screening criteria in the United Kingdom in identifying individuals with FH-causing variants, presenting a scalable screening criteria for general populations. Analysis included UK Biobank participants with whole exome sequencing, classifying them as having FH when (likely) pathogenic variants were detected in their LDLR, APOB, or PCSK9 genes. Data were stratified into 3 data sets for (1) feature importance analysis; (2) deriving state-of-the-art statistical and machine learning models; (3) evaluating models' predictive performance against clinical diagnostic and screening criteria: Dutch Lipid Clinic Network, Simon Broome, Make Early Diagnosis to Prevent Early Death, and Familial Case Ascertainment Tool. One thousand and three of 454 710 participants were classified as having FH. A Stacking Ensemble model yielded the best predictive performance (sensitivity, 74.93%; precision, 0.61%; accuracy, 72.80%, area under the receiver operating characteristic curve, 79.12%) and outperformed clinical diagnostic criteria and the recommended screening criteria in identifying FH variant carriers within the validation data set (figures for Familial Case Ascertainment Tool, the best baseline model, were 69.55%, 0.44%, 65.43%, and 71.12%, respectively). Our model decreased the number needed to screen compared with the Familial Case Ascertainment Tool (164 versus 227). Our machine learning-derived model provides a higher pretest probability of identifying individuals with a molecular diagnosis of FH compared with current approaches. This provides a promising, cost-effective scalable tool for implementation into electronic health records to prioritize potential FH cases for genetic confirmation.

Addressing comprehensive complexities a striking familial hypercholesterolemia case study.

Premature aortic involvement and comprehensive management strategies in familial hypercholesterolemia familial hypercholesterolemia (FH), a rare autosomal dominant genetic disorder, poses significant challenges due to its propensity for elevated low-density lipoprotein cholesterol, premature coronary heart disease, and vascular atherosclerosis. Unraveling Cardiovascular Complexities: A Striking Familial Hypercholesterolemia. This case study delves into a remarkable instance of FH in a 16-year-old female who presented with chest pain and worsening dyspnea. Diagnostic evaluation revealed distinct electrocardiographic changes, elevated troponin levels, and profound dyslipidemia. Remarkable findings on transthoracic echocardiography, computed tomography angiography, and catheterization prompted multidisciplinary interventions and demonstrated remarkable enhancements in ventricular function, mitral regurgitation, and aortic stenosis. The case study underscores the urgency of comprehensive management strategies in confronting the myriad challenges of FH, emphasizing the value of early intervention, innovative therapies, and rigorous imaging modalities for unraveling the intricate cardiovascular manifestations of this condition.

Recapitulating familial hypercholesterolemia in a mouse model by knock-in patient-specific LDLR mutation.

Familial hypercholesterolemia (FH) is one of the most prevalent monogenetic disorders leading to cardiovascular disease (CVD) worldwide. Mutations in Ldlr, encoding a membrane-spanning protein, account for the majority of FH cases. No effective and safe clinical treatments are available for FH. Adenine base editor (ABE)-mediated molecular therapy is a promising therapeutic strategy to treat genetic diseases caused by point mutations, with evidence of successful treatment in mouse disease models. However, due to the differences in the genomes between mice and humans, ABE with specific sgRNA, a key gene correction component, cannot be directly used to treat FH patients. Thus, we generated a knock-in mouse model harboring the partial patient-specific fragment and including the Ldlr W490X mutation. LdlrW490X/W490X mice recapitulated cholesterol metabolic disorder and clinical manifestations of atherosclerosis associated with FH patients, including high plasma low-density lipoprotein cholesterol levels and lipid deposition in aortic vessels. Additionally, we showed that the mutant Ldlr gene could be repaired using ABE with the cellular model. Taken together, these results pave the way for ABE-mediated molecular therapy for FH.

Like daughter, like mother: two cases of familial hypercholesterolaemia incidentally diagnosed during investigation of premature pubarche and obesity in a 6-year old girl

Like daughter, like mother: two cases of familial hypercholesterolaemia incidentally diagnosed during investigation of premature pubarche and obesity in a 6-year old girl

Prevalent Variants in the LDLR Gene Impair Responsiveness to Rosuvastatin among Family Members of Patients with Premature Myocardial Infarction.

Familial hypercholesterolemia (FH) is an inherited metabolic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-c) from birth. About 85% of all FH cases are caused by pathogenic variants in the LDLR gene. Individuals with FH have increased cardiovascular risk, including a high risk of premature myocardial infarction (PMI). We conducted an opportunistic exome screening to identify variants in the LDLR gene among Vietnamese patients with PMI treated at a general hospital in southern Vietnam. A cascade testing for LDLR variants was conducted in their relatives within three generations, and the effects of the LDLR variant on the response to rosuvastatin treatment were also studied using a comparative before-and-after study design on those who were eligible. A total of 99 participants from the three generations of four PMI patients were recruited, mean age 37.3 ± 18.5 years, 56.6% males. Sanger sequencing revealed two variants in the LDLR gene: variant rs577934998 (c.664T>C), detected in 17 individuals within one family, and variant rs12710260 (c.1060+10G>C), found in 32 individuals (49.5%) in the other three families tested. Individuals harboring the variant c.664T>C had significantly higher baseline LDL-c and total cholesterol levels compared to those with variant c.1060+10G>C (classified as benign) or those without LDLR variants, and among the 47 patients subjected to a 3-month course of rosuvastatin therapy, those with variant c.664T>C had a significantly higher risk of not achieving the LDL-c target after the course of treatment compared to the c.1060+10G>C carriers. These findings provide evidence supporting the existence of pathogenic LDLR variants in Vietnamese patients with PMI and their relatives and may indicate the need for personalizing lipid-lowering therapies. Further studies are needed to delineate the extent and severity of the problem.

Genetic association between vitamin D receptor gene and Saudi patients confirmed with Familial Hypercholesterolemia.

Familial Hypercholesterolemia (FH) is a common condition caused by inherited genetic abnormalities. Inadequate clearance of the circulating low-density lipoproteins (LDL) is the primary cause of the excessive concentrations of LDL seen in FH patients. The relation with vitamin D deficiency and vitamin D receptor (VDR) gene is well documented in the Saudi Arabia. The aim of this study was to investigate the role of molecular analysis studied between FH patients and fours polymorphisms associated with VDR gene in Saudi Population. In this case-control study, 120 patients were selected, and 50 patients were confirmed as FH and 70 subjects were confirmed as healthy controls. Genotyping was performed with polymerase chain reaction followed by restriction fragment length polymorphism analysis using ApaI, BsmI, TaqI and FokI polymorphisms in the VDR gene. The current study results confirmed no association between clinical characteristics studied between FH cases and controls (p>0.05). Hardy Weinberg Equilibrium analysis was present in ApaI and FokI polymorphisms (p<0.05). Only ApaI (C vs A: OR-15.1 (95% CI:5.78-39.41); p<0.001; AC+CC vs AA: OR-6.59 (95% CI:2.42-17.95); p=0.0006) and BsmI (G vs A: OR-2.88 (95% CI:1.54-5.38); p=0.0006 and AG+GG vs AA: OR-3.79 (95% CI:1.72-8.35); p=0.0007) polymorphisms showed both allele and genotype association between FH patients and controls. ANOVA analysis confirmed that TG levels were associated (p=0.02) with combination of heterozygous and homozygous genotypes present in all four polymorphisms studied in this population. ApaI and BsmI polymorphisms in the VDR gene showed association with FH patients in the Saudi Population.

Prevalence and factors associated with possible cases of familial hypercholesterolemia in Brazilian adults: a cross-sectional study

This study aimed to estimate the prevalence of possible cases of FH and analyze associated factors in the adult Brazilian population. Cross-sectional study with laboratory data from the Brazilian National Health Survey, with 8521 participants. Possible cases of FH were defined according to the Dutch Lipid Clinic Network criteria. The prevalence and 95% confidence intervals (95% CI) of possible cases of FH were estimated according to sociodemographic variables, lifestyle, diabetes, hypertension, altered tests, treatment and self-rated health. Logistic regression was used to analyze the associations. The prevalence of possible cases of FH was 0.96%, higher in women, between 45 and 59 years, white race/skin color and others, less education, people with diabetes, hypertension and total cholesterol ≥ 310 mg/dL. The presence of FH was positively associated with regular self-rated health (OR 1.96; 95% CI 0.99–3.84), poor/very poor (OR 3.02; 95% CI 1.30–7.03) and negatively with black race/skin color (OR 0.10; 95% CI 0.02–0.46) and complete elementary school, incomplete high school (OR 0.47; 95% CI 0.23–0.98) and complete high school and more (OR 0.45; 95% CI 0.21–0.95). FH affects 1:104 Brazilian adults, these findings contribute to understanding the burden of disease in Brazil. Due to the scarcity of studies on FH in low- and middle-income countries, further studies are desirable.

Genetic Spectrum and Cascade Screening of Familial Hypercholesterolemia in Routine Clinical Setting in Hong Kong.

Familial hypercholesterolemia (FH) is a prevalent but often underdiagnosed monogenic disorder affecting lipoprotein metabolism, and genetic testing for FH has not been widely conducted in Asia in the past. In this cross-sectional study of 31 probands (19 adults and 12 children) and an addition of 15 individuals (12 adults and 3 children), who underwent genetic testing and cascade screening for FH, respectively, during the period between February 2015 and July 2023, we identified a total of 25 distinct LDLR variants in 71.0% unrelated probands. Among the adult proband cohort, a higher proportion of genetically confirmed cases exhibited a positive family history of premature cardiovascular disease. Treatment intensity required to achieve an approximate 50% reduction in pretreatment low-density lipoprotein cholesterol (LDL-C) exhibited potentially better diagnostic performance compared to pretreatment LDL-C levels, Dutch Lipid Clinic Network Diagnostic Criteria (DLCNC) score, and modified DLCNC score. Adult individuals identified through cascade screening demonstrated less severe phenotypes, and fewer of them met previously proposed local criteria for FH genetic testing compared to the probands, indicating that cascade screening played a crucial role in the early detection of new cases that might otherwise have gone undiagnosed. These findings underscore the significance of genetic testing and cascade screening in the accurate identification and management of FH cases.

Detection of hidden cases of familial hypercholesterolemia in the Netherlands: a central laboratory data-driven strategy

Abstract Introduction Familial hypercholesterolemia (FH) is a common genetic disorder in which patients are at high risk for premature coronary artery disease (CAD) due to lifelong exposure to low-density lipoprotein cholesterol (LDL-C). Although early diagnosis and lipid lowering therapy (LLT) are essential to prevent adverse cardiovascular outcomes, FH patients remain globally underdiagnosed and undertreated, warranting novel screening methods to identify these patients. In the present study we aimed to evaluate whether existing central laboratory data can be utilized as a new method to detect undiagnosed FH patients. Additionally, we investigated the extent of underdiagnosis and undertreatment among patients with severe hypercholesterolemia in the Netherlands. Methods In this single-center, cross-sectional study, we selected individuals with at least one previously measured LDL-C plasma level ≥99.5th percentile for age and sex, from a central laboratory database containing lipid profiles of approximately 600.000 primary care patients. First, a blood sample was obtained to get more recent lipid values. Participating patients were subsequently asked to fill out a detailed questionnaire on medical and family history. Using these data, we calculated the Dutch Lipid Clinic Network (DLCN) criteria for each patient for the clinical diagnosis of FH. Results We identified a total of 5,100 patients with severe hypercholesterolemia (at least one LDL-C ≥99.5th percentile for age and sex) from the central laboratory database. Out of these, 1,206 patients (24%) participated in this study. Mean ± SD LDL-C corrected for LLT was 5.72 ± 1.83 mmol/L, 785 patients (65.1%) used LLT, and 150 patients (12.4%) had CVD in their medical history. In total, 131 patients (11%) had a persistent LDL-C ≥99.5th percentile for age and sex. DLCN criteria for phenotypic FH (DLCN score ≥6) were met by 302 patients (25%) of whom 39 patients (12.9%) had undergone prior genetic testing according to clinical guidelines. Of the 302 clinically diagnosed FH patients only 1 (0.3%) met the European Society of Cardiology (ESC) guideline recommending LDL-C targets &amp;lt;1.8 mmol/L in FH patients. Conclusion These data highlight the significant underdiagnosis and undertreatment of FH in the Netherlands, despite the fact that this country has a relatively high FH identification rate. We demonstrate that the use of central laboratory data is an effective strategy for identifying previously undetected cases of FH and eagerly await the genetic confirmation of the newly identified FH patients in this study, which will provide valuable insights into the genetic basis of this disorder and help further improve patient care.

Modelling a two-stage adult population screen for autosomal dominant familial hypercholesterolaemia: cross-sectional analysis within the UK Biobank

BackgroundMost people with autosomal dominant familial hypercholesterolaemia (FH) remain undetected, which represents a missed opportunity for coronary heart disease prevention.ObjectiveTo evaluate the performance of two-stage adult population screening for FH.DesignUsing...

Genetic backgrounds and diagnosis of familial hypercholesterolemia.

Lipid disorders play a critical role in the intricate development of atherosclerosis and its clinical consequences, such as coronary heart disease and stroke. These disorders are responsible for a significant number of deaths in many adult populations worldwide. Familial hypercholesterolemia (FH) is a genetic disorder that causes extremely high levels of LDL cholesterol. The most common mutations occur in genes responsible for low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9). While genetic testing is a dependable method for diagnosing the disease, it may not detect primary mutations in 20%-40% of FH cases.