Genetic Testing For Familial Hypercholesterolemia Research Articles

Expanded genetic testing in familial hypercholesterolemia—A single center's experience

ObjectiveAssess the yield of genetic testing for pathogenic variants in ABCG5, ABCG8, LIPA, and APOE in individuals with personal and family histories suggestive of familial hypercholesterolemia. MethodsRetrospective review of patients seen in the Advanced Lipid Disorders Clinic at Johns Hopkins ResultsIn the lipid clinic at a single center during the years 2015–2023, 607 patients underwent genetic testing for familial hypercholesterolemia, of which 263 underwent the expanded genetic testing for sitosterolemia. Eighty-eight patients had genetic testing which included APOE, and 22 patients had testing which included LIPA. Among these, one patient was identified to have a pathogenic variant in APOE and another patient with a pathogenic variant in ABCG5 (0.7 % yield). The frequency of a positive result was double that of a variant of uncertain significance. ConclusionThese data suggest in rare cases expanded testing can provide answers for patients and families with a minimal likelihood of a variant of uncertain significance.

Genetic Counseling and Genetic Testing for Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is one of the most common autosomal codominant Mendelian diseases. The major complications of FH include tendon and cutaneous xanthomas and coronary artery disease (CAD) associated with a substantial elevation of serum low-density lipoprotein levels (LDL). Genetic counseling and genetic testing for FH is useful for its diagnosis, risk stratification, and motivation for further LDL-lowering treatments. In this study, we summarize the epidemiology of FH based on numerous genetic studies, including its pathogenic variants, genotype-phenotype correlation, prognostic factors, screening, and usefulness of genetic counseling and genetic testing. Due to the variety of treatments available for this common Mendelian disease, genetic counseling and genetic testing for FH should be implemented in daily clinical practice.

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.

Possible explanations for the common clinical familial hypercholesterolemia phenotypes in the Faroe Islands

The prevalence of clinical familial hypercholesterolemia (FH) is very high in the Faroe Islands, but the possible causes are unknown. We aimed to describe potential genetic causes of FH in the Faroe Islands and to investigate whether levels of lipoprotein(a) and measures of dietary habits were associated with clinical FH in the Faroe Islands. In this case-control study, we identified potential clinical FH cases aged 18-75 years registered within a nationwide clinical laboratory database in the Faroe Islands and invited them for diagnostic evaluation according to clinical FH scoring systems. Controls were identified in the background population. Lipoprotein(a) was measured in plasma, while the fatty acid composition was determined in adipose tissue. The habitual diet of the participants was assessed using a food frequency questionnaire. Genetic testing for FH and polygenic variants was performed in a selection of clinical FH cases. A total of 121 clinical FH cases and 123 age- and sex-matched controls were recruited. We found a very low frequency of monogenic FH (2.5%), but a high level of polygenic FH (63%) in those genetically tested (67%). High levels of plasma lipoprotein(a) were associated with high odds of clinical FH. Clinical FH cases had a lower intake of saturated fatty acids (SFAs) measured by a high fat-score and a lower content of SFAs in adipose tissue compared with controls. The high prevalence of FH in the Faroe Islands may be due to polygenic causes of hypercholesterolemia and to a lesser extent other genetic factors and elevated plasma lipoprotein(a) levels.

Lipoprotein profile assessed by 1H NMR, BMI and blood pressure are associated with vascular alterations in children with familial hypercholesterolaemia

Background and aimsChildren with familial hypercholesterolaemia (FH) have elevated low-density lipoprotein cholesterol (LDL-C) concentrations since birth, which increases the risk of cardiovascular disease in adulthood. Arterial injury and stiffness parameters, including carotid intima media thickness (cIMT), pulse wave velocity (PWV) and distensibility (DIST), can be detected early in childhood. We studied the associations between cIMT, PWV and DIST with the lipoprotein profile assessed by proton nuclear magnetic resonance (1H NMR) and with influential variables such as blood pressure (BP) or body mass index (BMI) in children with FH. Methods and resultsIn this cross-sectional study, we included 201 children (96 with FH and 105 non-FH controls). Clinical history, physical examination and standard biochemical studies were performed. FH genetic testing was performed when clinically indicated. Carotid ultrasonography and an advanced lipoprotein profile by 1H NMR were performed. Multivariate and classification methods were used.There were no differences between cIMT, PWV and DIST between FH and non-FH children. FH children presented more total LDL and large, medium and small particles. Small LDL particles, BMI and systolic BP determined the presence of pathological IMT in the FH group. LDL size, high-density lipoproteins and very low-density lipoprotein particles together with blood pressure determined the presence of pathological arterial wall elasticity. ConclusionsAlterations in lipoprotein parameters assessed by are associated with early structural and functional arterial characteristics in children with FH. BMI and BP act as boosting factors. Cardiovascular prevention should start early in children with FH, encompassing all components of a healthy lifestyle.

Genetic Testing for Familial Hypercholesterolemia in a Pediatric Group: A Romanian Showcase.

Familial hypercholesterolemia (FH) is a genetic disease marked by high levels of LDL-cholesterol. This condition has long-term clinical implications, such as cardiovascular events, that are evident during adult life. Here, we report on a single-center cross-sectional showcase study of genetic testing for FH in a Romanian pediatric group. Genetic testing for FH was performed on 20 Romanian pediatric patients, 10 boys and 10 girls, admitted with LDL-cholesterol levels over 130 mg/mL to the National Institute for Mother and Child Health "Alesssandrescu-Rusescu" in 2020. Genetic testing was performed using the Illumina TruSight Cardio panel. We identified pathogenic/likely pathogenic variants that could explain the phenotype in 5/20 cases. The involved genes were LDLR and APOB. Clinical signs that suggest the diagnosis of FH are scarce for the pediatric patient, although it can be diagnosed early during childhood by lipid panel screening. Prevention could prove lifesaving for some of these patients.

Genetic Testing for Familial Hypercholesterolemia in Clinical Practice.

Genetic testing has proven utility in identifying and diagnosing individuals with FH. Here we outline the current landscape of genetic testing for FH, recommendations for testing practices and the efforts underway to improve access, availability, and uptake. Alternatives to the traditional genetic testing and counseling paradigm for FH are being explored including expanding screening programs, testing in primary care and/or cardiology clinics, leveraging electronic communication tools like chatbots, and implementing direct contact approaches to facilitate genetic testing of both probands and at-risk relatives. There is no consensus on if, when, and how genetic testing or accompanying genetic counseling should be provided for FH, though traditional genetic counseling and/or testing in specialty lipid clinics is often recommended in expert statements and professional guidelines. More evidence is needed to determine whether alternative approaches to the implementation of genetic testing for FH may be more effective.

Genetic testing for familial hypercholesterolemia in Quebec, Canada: a single-centre retrospective cohort study.

Familial hypercholesterolemia (FH) is associated with premature atherosclerotic cardiovascular disease caused by elevated low-density lipoprotein cholesterol (LDL-C) levels. We determined the impact of a full next-generation sequencing (NGS) genetic panel on reclassification of patients with a clinical diagnosis of FH in Quebec compared to the partial genetic panel currently offered by the Quebec Ministère de la Santé et des Services sociaux (Ministry of Health and Social Services) (MSSS), which includes 11 variants that are common in French Canadians. We conducted a retrospective cohort study in a subgroup of patients in the Canadian FH Registry seen at the McGill University Health Centre Preventive Cardiology/Lipid Clinic, Montréal, between September 2017 and September 2021 who were clinically diagnosed with severe hypercholesterolemia, probable FH or definite FH according to the Canadian definition of FH. Next-generation sequencing of the LDLR, APOB and PCSK9 genes, and multiplex ligation-dependent probe amplification of the LDLR gene to detect genetic variants, were performed. Among 335 consecutive patients with heterozygous FH (184 men [54.9%] and 151 women [45.1%]), the baseline LDL-C level was 6.96 (standard deviation 1.79) mmol/L. Patients identified through cascade screening were 11 years younger on average than index patients, and smaller proportions presented to the clinic with cardiovascular risk factors. A pathogenic FH variant was identified in 169 (73.8%) of the 229 patients who underwent genetic testing; the majority had variants in the LDLR (146 [86.4%]) or APOB (24 [14.2%]) gene. The genetic panel offered by the MSSS accounted for only 48% of the variants identified with the full NGS panel. Of the 229 patients, 90 (39.3%, 95% confidence interval 32.9%-46.0%) were reclassified from a clinical diagnosis of probable FH to definite FH after genetic screening with a full FH panel. Genetic testing in patients suspected of having FH provided diagnostic certainty and permitted many patients with a clinical diagnosis of probable FH to be reclassified as having definite FH. Genetic screening allows for increased identification of patients with FH and may therefore help reduce the burden of cardiovascular disease and mortality rates among Canadians with FH. Trial registration: ClinicalTrials.gov, no. NCT02009345.

The effect of adjusting LDL-cholesterol for Lp(a)-cholesterol on the diagnosis of familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) diagnostic tools help prioritise patients for genetic testing and include LDL-C estimates commonly calculated using the Friedewald equation. However, cholesterol contributions from lipoprotein(a) (Lp(a)) can overestimate 'true' LDL-C, leading to potentially inappropriate clinical FH diagnosis. To assess how adjusting LDL-C for Lp(a)-cholesterol affects FH diagnoses using Simon Broome (SB) and Dutch Lipid Clinic Network (DLCN) criteria. Adults referred to a tertiary lipid clinic in London, UK were included if they had undergone FH genetic testing based on SB or DLCN criteria. LDL-C was adjusted for Lp(a)-cholesterol using estimated cholesterol contents of 17.3%, 30% and 45%, and the effects of these adjustments on reclassification to 'unlikely' FH and diagnostic accuracy were determined. Depending on the estimated cholesterol content applied, LDL-C adjustment reclassified 8-23% and 6-17% of patients to 'unlikely' FH using SB and DLCN criteria, respectively. The highest reclassification rates were observed following 45% adjustment in mutation-negative patients with higher Lp(a) levels. This led to an improvement in diagnostic accuracy (46% to 57% with SB, and 32% to 44% with DLCN following 45% adjustment) through increased specificity. However all adjustment factors led to erroneous reclassification of mutation-positive patients to 'unlikely' FH. LDL-C adjustment for Lp(a)-cholesterol improves the accuracy of clinical FH diagnostic tools. Adopting this approach would reduce unnecessary genetic testing but also incorrectly reclassify mutation-positive patients. Health economic analysis is needed to balance the risks of over- and under-diagnosis before LDL-C adjustments for Lp(a) can be recommended.

Severe hypercholesterolemia in a patient with very low albumin and normal renal function

A 20-year-old male presented with severe elevation in low-density lipoprotein cholesterol (LDL-C). Initial genetic testing for familial hypercholesterolemia was negative. Patient also had low albumin, and further genetic testing showed homozygous variants in the ALB gene, suggesting congenital analbuminemia (CAA) causing severe hyperlipidemia. CAA is an autosomal recessive disorder with incidence of about 1:1,000,000. The gene for albumin is a single autosomal gene, and pathological variants that affect splicing lead to premature stop, nonsense variants, and deletions that result in a defect in albumin synthesis with CAA. CAA can be fatal in the prenatal period and cause infections in early childhood. CAA is tolerated better in adulthood because of compensatory increase in other plasma proteins. Plasma lipoproteins also increase, and CAA can cause gross hyperlipidemia with severe elevations in LDL-C and hypercholesterolemia. Genetic examination of ALB is mandatory to establish the diagnosis. Early diagnosis may be important to initiate lipid-lowering treatments to avoid premature coronary artery disease.

Genetic testing for familial hypercholesterolaemia: utility beyond diagnosis.

Genetic testing for familial hypercholesterolaemia: utility beyond diagnosis.

Awareness of positive genetic testing for familial hypercholesterolemia encourages better adherence to triple-combined lipid-lowering therapy

Background and Aims : To assess the impact of awareness of genetic testing for familial hypercholesterolemia (FH) on the adherence to the lipid-lowering therapy (LLT).Methods: Patients ≥18 y.o. with “probable” or “definite” FH according to the DLCN criteria were included (n=82). The study consists of three visits (follow-up is 6 months) with a block randomization with a 2:1 allocation ratio (with: without genetic testing). The results of genetic testing were reported at the second visit. Patients were divided into 3 groups: I - with "positive" genetic testing (n=38); II - with "negative" genetic testing (n=19); III - without genetic testing (n=25). Fisher's test was used for statistical analysis. The study was registered on ClinicalTrials (NCT04656028).Results: Individuals with FH variants knew more often their LDL-C target level (61.1% at visit 3 vs 26.3% at visit 2; p=0.004) and comparing with group II (17.6%) by visit 3 (p=0.006). There was no difference in the proportion of patients taking combined LLT (statin+ezetimibe+PCSK9i) at the first visit (5.3% at groups I and II, 12.0% at group III; p=0.556) and in the frequencies of its prescribing at the second visit (70.3% at group I, 52.6% at group II and 56.0% at group III; p=0.326). Only patients with FH variants began to take the combined LLT significantly more often by visit 3 (43.2% vs 5.3% at visit 1 (p <0.001)).Conclusions: Knowledge of positive genetic testing for FH contributes to a better knowing of the LDL-C target level and better adherence to the triple-combined LLT. Background and Aims : To assess the impact of awareness of genetic testing for familial hypercholesterolemia (FH) on the adherence to the lipid-lowering therapy (LLT). Methods: Patients ≥18 y.o. with “probable” or “definite” FH according to the DLCN criteria were included (n=82). The study consists of three visits (follow-up is 6 months) with a block randomization with a 2:1 allocation ratio (with: without genetic testing). The results of genetic testing were reported at the second visit. Patients were divided into 3 groups: I - with "positive" genetic testing (n=38); II - with "negative" genetic testing (n=19); III - without genetic testing (n=25). Fisher's test was used for statistical analysis. The study was registered on ClinicalTrials (NCT04656028). Results: Individuals with FH variants knew more often their LDL-C target level (61.1% at visit 3 vs 26.3% at visit 2; p=0.004) and comparing with group II (17.6%) by visit 3 (p=0.006). There was no difference in the proportion of patients taking combined LLT (statin+ezetimibe+PCSK9i) at the first visit (5.3% at groups I and II, 12.0% at group III; p=0.556) and in the frequencies of its prescribing at the second visit (70.3% at group I, 52.6% at group II and 56.0% at group III; p=0.326). Only patients with FH variants began to take the combined LLT significantly more often by visit 3 (43.2% vs 5.3% at visit 1 (p <0.001)). Conclusions: Knowledge of positive genetic testing for FH contributes to a better knowing of the LDL-C target level and better adherence to the triple-combined LLT.

Genetic testing for familial hypercholesterolemia using low-cost high-throughput microarray-based genotyping

Background and Aims : Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease (CVD). Current methods for genetically confirming FH are expensive and time-consuming. In this study we set out to validate a low cost, high throughput genotyping array, dubbed GOALL-GSA_v1, developed to detect known FH-causing single-nucleotide variants (SNVs), small indels and copy number variations (CNV) (∼€30 per sample) in a cohort of genetically diagnosed FH patients.

Integrating Patient-Reported Outcomes Into Clinical Genetic Testing for Familial Hypercholesterolemia.

Patient-reported outcomes (PROs) and PRO measures (PROMs) are often used to help clinicians and researchers understand patients' personal concerns, feelings, experiences, and perspectives following the implementation of an intervention. Notably, PROs and PROMs can inform health systems, health policy, and payers on the utility of clinical genetic testing based on each patient's personal values, perspectives, and potential health behaviors subsequent to testing. In this topic synopsis, we discuss the underexplored role of and implications for PROs and PROMs following genetic testing for familial hypercholesterolemia (FH), an autosomal dominant genetic disorder of cholesterol metabolism that can lead to highly premature fatal and nonfatal myocardial infarction and stroke. We also discuss why the use and consideration of patient perspectives, via PROs and PROMs, are critical to the process of optimizing patient care across various FH treatment contexts. As expert clinician groups consider the latest evidence when establishing recommendations for FH genetic testing, there is a ripe opportunity for clinicians and researchers to explore the value and utility of PROs to inform and possibly improve care for patients diagnosed with FH.

Case-finding and genetic testing for familial hypercholesterolaemia in primary care

ObjectiveFamilial hypercholesterolaemia (FH) is a common inherited disorder that remains mostly undetected in the general population. Through FH case-finding and direct access to genetic testing in primary care, this intervention...

Frequency of Lipoprotein (a) Single Nucleotide Polymorphisms in patients undergoing Familial Hypercholesterolaemia genetic testing

Frequency of Lipoprotein (a) Single Nucleotide Polymorphisms in patients undergoing Familial Hypercholesterolaemia genetic testing

Patient-Reported Outcomes following Genetic Testing for Familial Hypercholesterolemia, Breast and Ovarian Cancer Syndrome, and Lynch Syndrome: A Systematic Review.

Background: Patient-reported outcomes (PROs) and PRO measures (PROMs) are real-world evidence that can help capture patient experiences and perspectives regarding a clinical intervention such as genetic testing. Objective: To identify and capture methods and qualitative PRO themes among studies reporting PROs following genetic testing for FH, breast and ovarian cancer syndrome, and Lynch syndrome. Methods: A systematic review was conducted via PubMed/MEDLINE, EMBASE, and Yale University’s TRIP Medical Databases on articles published by April 2021. Results: We identified 24 studies published between 1996 and 2021 representing 4279 participants that reported PROs following genetic testing for FH, breast and ovarian cancer syndrome, and Lynch syndrome. Studies collected and reported PROs from validated PROM instruments (n = 12; 50%), validated surveys (n = 7; 26%), and interviews (n = 10; 42%). PRO themes ranged across all collection methods (e.g., psychological, knowledge, coping and satisfaction, concern about stigma/discrimination, etc.). Conclusions: Important gaps identified include (1) most studies (n = 18; 75%) reported PROs following genetic testing for breast and ovarian cancer, and (2) populations reporting PROs overall were largely of White/Caucasian/Northern European/Anglo-Saxon descent. We offer recommendations and describe real-world implications for the field moving forward.

Cost-effectiveness of cascade genetic testing for familial hypercholesterolemia in the United States: A simulation analysis

Objective There is no coordinated cascade testing program for familial hypercholesterolemia (FH) in the U.S. We evaluated the contemporary cost-effectiveness of cascade genetic testing relatives of FH probands with a pathogenic variant. MethodsA simulation model was created to simulate multiple family trees starting with progenitor individuals carrying a pathogenic variant for FH who were followed through several generations. This approach allowed us to examine a family tree that had grown sufficiently to have large numbers of relatives across multiple degrees of relatedness. The model estimated costs and life years gained (LYG) when cascade genetic testing was implemented for relatives of FH probands identified through standard care who were at or older than designated age thresholds (5, 10, 15, 20, 25, 30, 35, 40). Costs were valued in 2018 U.S. dollars. Future costs and LYG projected by the model were discounted at an annual rate of 3%. ResultsFor 1st degree relatives, cascade testing at every age threshold resulted in a positive number of average LYG per person, though this number decreased as testing was started at higher age thresholds. Testing was not cost-effective if initiated at an age threshold of 40 and older but was cost-effective at younger age thresholds, with a discounted cost per LYG per person of less than $50,000. For 2nd degree relatives, testing was cost-effective with a screening age threshold of 10 but no longer cost-effective at a threshold of 15 or higher. In more distant relatives, cascade genetic testing was not beneficial or cost-effective. ConclusionsBased on our simulation model, cascade genetic testing for FH in the U.S. is cost-effective if started before age 40 in 1st degree relatives and before age 15 in 2nd degree relatives.

Genetic testing for familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is a codominant genetic disorder causing premature atherosclerotic cardiovascular disease (ASCVD). It is common, affecting 1 in 250 individuals worldwide and of the ∼100,000 Australians estimated to have FH, most are undiagnosed and treatment is often suboptimal. Several scoring algorithms based on low-density lipoprotein-cholesterol (LDL-C) levels, physical findings, and elements of personal and family history, help clinicians diagnose FH at varying levels of confidence ranging from possible to definite. Targeted DNA sequencing to identify the underlying pathogenic variant in any of the three FH genes (LDLR, APOB, and PCSK9) has become more accessible, but it is not essential for diagnosis of FH, and is currently not widely used. However, identification of a pathogenic variant is considered the ‘gold standard’ for FH diagnosis. Expanded FH panels can identify pathogenic variants in other hypercholesterolaemia genes, such as APOE, LIPA, and ABCG5/8. FH cascade screening is recommended to identify affected family members, and the benefits of early intervention to lower LDL-C and reduce the associated ASCVD burden are clear. National registries can also play a key role in identifying patients with FH. FH genetic testing should be incorporated as standard of care for patients and their relatives with suspected FH.

Genetic testing for familial hypercholesterolaemia

Genetic testing for familial hypercholesterolaemia