Cascade Screening Research Articles

Abstract 13180: Cardiovascular Disease and Cholesterol Lowering Therapy in Women and Men With Molecularly Proven Familial Hypercholesterolemia

Introduction: Familial Hypercholesterolemia (FH) is an autosomal dominant disease affecting women and men on the same proportion. There is scant evidence on cardiovascular disease (CVD) and therapy adequacy on contemporary FH cohorts according to sex. Goals: Evaluate whether there were differences in CVD outcomes and treatment intensity in women and men with molecularly proven FH at a specialized lipid clinic. Methods: Initially a cross-sectional analysis of 801 patients with FH enrolled between 2011 and 2022 on a genetic cascade screening program was done . All had a positive FH molecular diagnosis. Participants were then followed by a median of 5 years (0.08 to 11 years). Clinical, laboratory and, treatment parameters were compared at baseline and during follow-up according to sex. Results: The cohort consisted of 455 women (57%) and 346 men (43%), mean age 47± 15 years. At baseline there were no sex differences regarding LDL-C (196±74 mg/dL men vs 200±75 mg/dL women, p= 0.567) as well as percentage of those with LDL-C < 100 mg/dL (6.8% men vs 6.1% women, p=0.712) or < 70 mg/dL at baseline (0.3% men vs 0% women, p=0.238). Intensive lipid lowering treatment use was similar between men and women at baseline (75.1% vs. 74.4%; p= 0.848) and during follow-up (87.6% vs. 88.3%; p= 0.785). At baseline 23.1% of women and 38.1% of men had a previous history of CVD (p= 0.000). After follow-up, 41 women (9%) and 52 men (15%) had an incident CVD event (p=0.009). Multivariate Cox regression analysis showed that risk factors related to incident events were age (HR=1.028, 95% CI 1.005-1.052 per year, p =0.019), presence of corneal arcus (HR 1.794, 95% CI 1.096-2.937, p= 0.02), current smoking (HR 2.534, 95% CI 1.304-4.927, p=0.006) and a previous CVD event (HR= 1.793, 95%CI 1.041-3.087, p= 0.035). Conclusions: Overall FH men had a greater risk of CVD events than FH women. There was no difference in treatment intensity and CVD outcomes were associated with traditional risk factors or previous CVD.

Abstract 16147: Racial and Ethnic Differences in the Diagnostic Yield of Cardiomyopathy, Aortopathy, and Arrhythmia Genetic Testing and Frequency of Family Variant Screening

Introduction: Genetic testing for individuals with inherited cardiovascular conditions can guide treatment and aid in family screening. However, the diagnostic yield of pathogenic or likely pathogenic (P/LP) variants may differ by race and ethnicity because of a lack of diversity in population-based genomic databases. Methods: We evaluated the diagnostic yield (% tests with P/LP variants) of genetic testing for cardiomyopathy, aortopathy, and arrhythmia among probands undergoing testing at a large commercial laboratory (Invitae Corp.) from 9/2015-7/2022 for the most common racial and ethnic groups: Hispanic, Non-Hispanic (NH) Black, and NH White individuals. We used multivariable logistic regression to evaluate for differences in diagnostic yield by race and ethnicity adjusting for age, sex, payer, and number of genes tested. The ratio of the number of persons undergoing family variant testing (FVT) to the number with positive tests was determined, with Chi-square tests to evaluate for differences by group. Results: We identified 129,565 persons undergoing diagnostic genetic testing (n=9,157 Hispanic, n=16,287 NH Black, and n=78,740 NH White). Compared with White persons, the odds of a positive test were higher in Black and Hispanic persons for cardiomyopathy (OR 1.2, 95% CI 1.2-1.3, p <0.001 and OR 1.3, 95% CI 1.2-1.4, p <0.001, respectively) and aortopathy (OR 2.1, 95% CI 1.8-2.5, p <0.001 and OR 1.9, 95% CI 1.7-2.2, p <0.001, respectively), and higher for Hispanic persons for arrhythmia (OR 1.2, 95% CI 1.1-1.3, p <0.001). The ratio of FVT to positive tests was significantly (p < 0.001) lower for Black and Hispanic persons than White persons for cardiomyopathy (0.32, 1.19, and 1.51, respectively), aortopathy (0.77, 1.62, and 2.34, respectively), and arrhythmia (1.47, 2.23, and 3.33, respectively). Conclusion: Despite being underrepresented in population genomic databases, the diagnostic yield of genetic screening for cardiomyopathy and aortopathy was higher in Black and Hispanic persons compared with White individuals. The relative frequency of family variant testing was lower in Black and Hispanic than in White persons, indicating an opportunity to improve cascade screening in these groups.

Abstract 13186: Factors Associated With Dysglycemia and Type 2 Diabetes Mellitus Onset in Familial Hypercholesterolemia

Introduction: Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disorder characterized by high blood LDL-C and cardiovascular disease (CVD). Type 2 diabetes mellitus (T2DM) is an independent cause of CVD and there is evidence that FH is associated with a lower frequency of its development. On the other hand, lipid lowering therapy (LLT) may increase T2DM risk. Goals: Evaluate the risk of dysglycemia and T2DM development in a cohort of molecularly proven FH individuals. Methods: This is a prospective analysis of a population enrolled on a genetic cascade screening program evaluated from March 2011 to January 2022. FH diagnosis was confirmed by molecular testing of variants in LDLR, APOB and PCSK9. Dysglycemia and T2DM diagnoses were done according to the ADA Criteria or use of any antidiabetic drugs. Results: 790 FH patients were included (age 45.5±15.0 years, 56.8% female, baseline LDL-C 198±74 mg/dL), 96.6% had LDLR variants. The prevalence of T2DM was 13.3% and 67.4% were taking LLT at baseline . There were 206 (26%) new cases of T2DM or dysglycemia after a median 51-month follow-up . In multivariate Cox regression analysis age (HR:1.026, CI95%: 1.014-1.038, p=0.000) , body mass index (HR: 1.062, CI95%: 1.035-1.090, p=0.000) and current smoking (HR: 2.005, HR: 1.337-3.008, p=0.001) were independently associated with T2DM and dysglycemia, while metformin use was associated with a lower risk (HR: 0.147, CI95%: 0.076-0.284, p=0.000). History of previous CVD, use of lipid lowering therapy at baseline, high intensity LLT , or type of molecular defect were not associated with higher T2DM/dysglycemia risk. Conclusions: In this cohort of molecularly proven FH subjects, T2DM affected more than 1 in 10 people at baseline. Previous CVD and classical risk factors but neither molecular defects nor lipid lowering therapy were associated with T2DM/dysglycemia onset.

Abstract 13631: Desmoplakin Cardiomyopathy in Pediatric Patients - A Distinct, Underrecognized Cohort of Arrhythmogenic Cardiomyopathy

Introduction: Arrhythmogenic cardiomyopathy is a spectrum of diagnoses including the historically recognized arrhythmogenic right ventricular cardiomyopathy. More recent literature describes predominately left ventricular (LV) or biventricular (BiV) involvement. Variants in the desmoplakin ( DSP) gene commonly cause LV and BiV phenotypes, though data in children are sparse. Hypothesis: Pediatric patients (pts) with DSP mutation have predominantly LV or BiV disease and may present with early onset malignant arrhythmia. Methods: We performed a multicenter, retrospective cohort study of pts <21 years with pathogenic or likely pathogenic DSP variants from 6 tertiary referral children’s hospitals. We describe clinical variation in DSP probands (PBs), the first affected family member prompting genetic testing due to clinical history, as compared to genotype-positive family members (FMs) <21 years of age diagnosed by familial cascade screening. Results: We identified 34 pts; 12 (35%) were PBs and 22 (65%) were FMs. Median age at genetic diagnosis was 13.3 and 12.3 years for PBs and FMs, respectively. Four PBs had LV-predominant disease; 6 had BiV disease (table 1). The most common initial diagnosis for PBs was myocarditis and dilated cardiomyopathy. ECG abnormalities were common in PBs (75%) and included left axis deviation, inferolateral T-wave inversion, and low QRS complex amplitude. The LV ejection fraction (EF) on echo was 48% and 65% for PBs and FMs, respectively. Eight PBs underwent MRI and 6 had late gadolinium enhancement involving the LV only, while 2 had BiV involvement. Six PBs underwent ICD implantation and 2 received appropriate ICD therapy (LVEF 25% and 41%). Two PBs had cardiac transplantation. Conclusion: Pediatric DSP -cardiomyopathy has predominantly LV or BiV involvement and may be misdiagnosed as myocarditis or dilated cardiomyopathy. Probands in particular, may present with early malignant ventricular arrhythmias and significant LV dysfunction.

Abstract 16981: A Machine Learning Model Increases Genetic Confirmation of UKB Participants With Suspected Monogenic Cardiovascular Disease

Introduction: Monogenic cardiovascular diseases (MCVDs) are collectively common yet highly underdiagnosed. Genetic testing for pathogenic variants can facilitate diagnosis and familial screening of MCVDs. Yet, most genetic variants within MCVD-associated genes currently annotated in ClinVar are variants of uncertain significance (VUS). VUS clinical utility is limited as VUS cannot be used for genetic confirmation of disease or for familial cascade screening. We previously developed a disease- and tissue-specific machine learning model for reclassification of VUS (Cardiovascular Disease-Pathogenicity Predictor [CVD-PP]). We sought to determine if use of CVD-PP on VUS identified through whole exome sequencing (WES) would increase genetic diagnosis of patients suspected of having a MCVD in the UK Biobank (UKB) cohort. Methods: We filtered for variants in 47 genes associated with 5 MCVDs (cardiomyopathies, channelopathies, aortopathies, cardiac amyloidosis, and familial hypercholesterolemia) in UKB participants with WES data. Participants harboring an American College of Medical Genetics confirmed ClinVar pathogenic or likely pathogenic (P/LP) variant in one of these genes were excluded. Phenotyping for presence of MCVDs was performed using EHR, clinical, cardiac imaging, and ECG data. CVD-PP was utilized to predict the pathogenicity of variants that were classified as VUS, had conflicting interpretations, or were absent from ClinVar. Results: Of participants with QC’ed WES data in UKB (n=452,933), 34.7% (n=157,030) had expression of a MCVD. Of these, 0.51% (n=799) carried a P/LP variant in a MCVD gene. Of the remaining P/LP variant-negative participants expressing disease (n=156,231), 4.1% (n=6,346) carried a VUS or non-ClinVar variant that was predicted pathogenic by CVD-PP. Conclusion: We demonstrate the potential utility of using a disease-and tissue-specific computational tool, CVD-PP, for deeper characterization of VUS in MCVD genes. Prioritization of CVD-PP-predicted pathogenic variants increases yield of genetic diagnosis in patients with evidence of clinical MCVDs from 0.51% using only ClinVar P/LP variants to 4.6% in UKB. This work provides a potential framework for increasing overall diagnostic yield of MCVDs.

Predictive Modeling and Structure Analysis of Genetic Variants in Familial Hypercholesterolemia: Implications for Diagnosis and Protein Interaction Studies.

Familial hypercholesterolemia (FH) is a hereditary condition characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C), which increases the risk of cardiovascular disease if left untreated. This review aims to discuss the role of bioinformatics tools in evaluating the pathogenicity of missense variants associated with FH. Specifically, it highlights the use of predictive models based on protein sequence, structure, evolutionary conservation, and other relevant features in identifying genetic variants within LDLR, APOB, and PCSK9 genes that contribute to FH. In recent years, various bioinformatics tools have emerged as valuable resources for analyzing missense variants in FH-related genes. Tools such as REVEL, Varity, and CADD use diverse computational approaches to predict the impact of genetic variants on protein function. These tools consider factors such as sequence conservation, structural alterations, and receptor binding to aid in interpreting the pathogenicity of identified missense variants. While these predictive models offer valuable insights, the accuracy of predictions can vary, especially for proteins with unique characteristics that might not be well represented in the databases used for training. This review emphasizes the significance of utilizing bioinformatics tools for assessing the pathogenicity of FH-associated missense variants. Despite their contributions, a definitive diagnosis of a genetic variant necessitates functional validation through in vitro characterization or cascade screening. This step ensures the precise identification of FH-related variants, leading to more accurate diagnoses. Integrating genetic data with reliable bioinformatics predictions and functional validation can enhance our understanding of the genetic basis of FH, enabling improved diagnosis, risk stratification, and personalized treatment for affected individuals. The comprehensive approach outlined in this review promises to advance the management of this inherited disorder, potentially leading to better health outcomes for those affected by FH.

Concordance of a High Lipoprotein(a) Concentration Among Relatives

Lipoprotein(a) (Lp[a]) concentrations are a highly heritable and potential causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Recent consensus statements by the European Atherosclerosis Society and American Heart Association recommend screening of relatives of individuals with high Lp(a) concentrations, but the expected yield of this approach has not been quantified in large populations. To measure the prevalence of high Lp(a) concentrations among first- and second-degree relatives of individuals with high Lp(a) concentrations compared with unrelated participants. In this cross-sectional analysis, pairs of first-degree (n = 19 899) and second-degree (n = 9715) relatives with measured Lp(a) levels from the UK Biobank study and random pairs of unrelated individuals (n = 184 764) were compared. Data for this study were collected from March 2006 to August 2010 and analyzed from December 2021 to August 2023. Serum Lp(a) levels, with a high Lp(a) level defined as at least 125 nmol/L. Concordance of clinically relevant high Lp(a) levels in first- and second-degree relatives of index participants with high Lp(a) levels. A total of 52 418 participants were included in the analysis (mean [SD] age, 57.3 [8.0] years; 29 825 [56.9%] women). Levels of Lp(a) were correlated among pairs of first-degree (Spearman ρ = 0.45; P < .001) and second-degree (Spearman ρ = 0.22; P < .001) relatives. A total of 1607 of 3420 (47.0% [95% CI, 45.3%-48.7%]) first-degree and 514 of 1614 (31.8% [95% CI, 29.6%-34.2%]) second-degree relatives of index participants with high Lp(a) levels also had elevated concentrations compared with 4974 of 30 258 (16.4% [95% CI, 16.0%-16.9%]) pairs of unrelated individuals. The concordance in high Lp(a) levels was generally consistent among subgroups (eg, those with prior ASCVD, postmenopausal women, and statin users). The odds ratios for relatives to have high Lp(a) levels if their index relative had a high Lp(a) level compared with those whose index relatives did not have high Lp(a) levels were 7.4 (95% CI, 6.8-8.1) for first-degree relatives and 3.0 (95% CI, 2.7-3.4) for second-degree relatives. The findings of this cross-sectional study suggest that the yield of cascade screening of first-degree relatives of individuals with high Lp(a) levels is over 40%. These findings support recent recommendations to use this approach to identify additional individuals at ASCVD risk based on Lp(a) concentrations.

Exploring Barriers and Facilitators to Indirect Cascade Screening for Familial Hypercholesteraemia in a Paediatric/Parent Population.

Familial hypercholesteraemia (FH), an inherited disorder of cholesterol metabolism, has a prevalence of 1:250 and an associated 6- to 22-fold increased risk for cardiovascular disease. Despite the prevalence and availability of effective risk-reduction treatments, 90% of at-risk Canadians are undiagnosed. Indirect cascade screening from an index case is useful but the uptake is low (<4%), suggesting that barriers may exist. Using the Theoretical Domains Framework, we sought to determine barriers and facilitators among parents of children diagnosed with FH that may influence the uptake of cascade screening among families. A qualitative description approach was used for virtual interviews with 10 parents of children with FH, recruited from a regional Lipid Clinic in Toronto, Canada. Semistructured interviews were conducted. The data were analysed using a directed content analysis method. Five interconnecting themes were identified that captured both facilitators and barriers of indirect cascade screening: a high level of knowledge about FH after clinic attendance; parents' surprise of their child's diagnosis and ongoing worry; parents' willingness to communicate the need for cholesterol screening; parents' desire for educational materials, dictated by an external vs internal locus of control; and social and societal influences including the lack of awareness about FH in professional and public domains. The themes identified will inform next steps in programme development. An urgent need was identified for strategies to educate the public and primary care providers about FH and blood cholesterol/genetic screening.

Genetic screening for hereditary transthyretin amyloidosis with polyneuropathy in western Sicily: Two years of experience in a neurological clinic.

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is caused by mutations in the TTR gene, leading to misfolded monomers that aggregate generating amyloid fibrils. A prospective systematic genetic screening for ATTRv-PN was proposed in patients presenting with a sensory-motor idiopathic polyneuropathy and two or more "red flags" among the following: family history of polyneuropathy or cardiopathy, bilateral carpal tunnel syndrome, cardiac insufficiency, renal amyloidosis, lumbar tract stenosis, autonomic dysfunction, idiopathic gastrointestinal disease, amyloid deposits on biopsy, and vitreous opacities. The detection rate was calculated, and nonparametric analyses were carried out to underline differences among screened positive versus negative patients. In the first step, 145 suspected patients underwent genetic testing, revealing a diagnosis of ATTRv-PN in 14 patients (10%). Then, cascade screening allowed early recognition of 33 additional individuals (seven symptomatic ATTRv-PN patients and 26 presymptomatic carriers) among 84 first-degree relatives. Patients with a positive genetic test presented a higher frequency of unexplained weight loss, gastrointestinal symptoms, and family history of cardiopathy. A systematic screening for ATTRv-PN yielded an increased recognition of the disease in our neurological clinic. Unexplained weight loss associated with axonal polyneuropathy had the highest predictive value in the guidance of clinical suspicion. A focused approach for the screening of ATTRv-PN could lead to an earlier diagnosis and identification of asymptomatic carriers, who will be promptly treated after a strict follow-up at the clinical onset.

Low-Cost High-Throughput Genotyping for Diagnosing Familial Hypercholesterolemia.

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. An Illumina Global Screening Array was customized to include probes for 636 variants, previously classified as FH-causing variants. First, its theoretical coverage was assessed in all FH variant carriers diagnosed through next-generation sequencing between 2016 and 2022 in the Netherlands (n=1772). Next, the performance of the array was validated in another sample of FH variant carriers previously identified in the Dutch FH cascade screening program (n=1268). The theoretical coverage of the array for FH-causing variants was 91.3%. Validation of the array was assessed in a sample of 1268 carriers of whom 1015 carried a variant in LDLR, 250 in APOB, and 3 in PCSK9. The overall sensitivity was 94.7% and increased to 98.2% after excluding participants with variants not included in the array design. Copy number variation analysis yielded a 89.4% sensitivity. In 18 carriers, the array identified a total of 19 additional FH-causing variants. Subsequent DNA analysis confirmed 5 of the additionally identified variants, yielding a false-positive result in 16 subjects (1.3%). The FH genotyping array is a promising tool for genetically diagnosing FH at low costs and has the potential to greatly increase accessibility to genetic testing for FH. Continuous customization of the array will further improve its performance.

A Practical Guide to Genetic Testing in Inherited Heart Disease.

Genetic testing has increasingly been shown to provide critical information regarding the treatment and management of patients with hereditary cardiomyopathies and arrhythmias and is available for a wide variety of conditions. It can provide information regarding arrhythmia risk, lifestyle recommendations, such as exercise avoidance, pharmaceutical therapies, and prognosis. Beyond the proband, genetic testing can be a valuable tool for cascade screening in the family. Genetic testing should be accompanied with genetic counseling, as genetic tests should be accompanied by expert interpretation, support in cascade family evaluation, and psychosocial considerations. Overall, it should be routinely implemented in arrhythmia and cardiomyopathy clinics.

Incidence of familial hypercholesterolemia in patients with early manifestations of coronary artery disease: data from a Russian multicenter study and meta-analysis

Aim. To assess the possibility of familial hypercholesterolemia (FH) detection among patients with early coronary artery disease (CAD) in practice in comparison with data from different populations. Patients with early manifestations of CAD are a promising group for identifying a proband with FH and subsequent cascade screening. The question remains open about the sufficiency of clinical criteria for diagnosing this disease.Material and methods. We examined 651 patients with CAD manifestations aged £55 years in men and £60 years in women. FH was diagnosed according to the Dutch Lipid Clinic Network (DLCN) criteria, and cardiovascular risk was assessed using the Montreal-FH-SCOR E. In 35 phenotype-positive patients with FH, as well as 5 with lowdensity lipoprotein cholesterol levels ³5,5 mmol/l and 23 with age of manifestation of coronary artery disease £35 years, the coding sequence of the genes for apolipoprotein B (APOB), low-density lipoprotein receptor (LDLR), low-density lipoprotein receptor adapter protein 1 (LDLRAP1), proprotein convertase subtilisin/kexin type 9 (PCSK9).Results. Definite FH was in 8 (1,2%), probable in 27 (4.2%), possible in 339 (52,1%) patients, while 277 (42,5%) patients had DLCN score of &lt;3 points; 31 (88,6%), of 35 phenotype-positive patients had a high Montreal-FH-SCORE risk. Six carriers of pathogenic variants were identified, 2 of which were among phenotype-negative patients. A meta-analysis of 16 studies with 13065 patients (2012-2023) showed that the incidence of FH is 5,22 (4,848-5,619)% (fixed model) and 5,93 (4,528-7,515)% (random model).Conclusion. The use of existing diagnostic scales does not provide guaranteed detection of FH among patients with early CAD. It is likely that DLCN modification by additional gradation of the criterion for the age of CAD manifestation will help increase its diagnostic value.

Does a proactive procedure lead to a higher uptake of predictive testing in families with a pathogenic BRCA1/BRCA2 variant? A family cancer clinic evaluation.

The uptake of genetic counseling and predictive genetic testing by family members at risk for hereditary tumor syndromes is generally below 50%. To address this issue, a new guideline was introduced in the Netherlands in 2019 that aims to improve the sharing of information within families. In addition to cascade screening supported by follow-up telephone calls with the proband, municipal records were accessed to allow the geneticist to contact at-risk family members directly. We evaluated this procedure in 32 families with a (likely) pathogenic germline BRCA1/BRCA2 variant diagnosed at our hospital between May 1, 2020, and July 31, 2021, comparing current uptake with outcomes achieved for 33 families diagnosed in 2014. Fifteen months after diagnostic testing of the proband, the uptake was 43% (120/277), comparable to the 44% (87/200) registered previously. Among a subgroup of women at 50% risk aged 25-75 years, 71% (47/66) were tested, comparable to an earlier uptake of 69% (59/86). Of the 34 at-risk relatives we contacted directly, 17 (50%) underwent predictive testing. In conclusion, we found no evidence that the new procedure leads to a substantially increased uptake. Future research should be primarily aimed at understanding intrafamilial communication barriers.

Cardiac Genetic Investigation of Sudden Infant and Early Childhood Death: A Study From Victims to Families.

Background Sudden infant death syndrome (SIDS) is the leading cause of death up to age 1. Sudden unexplained death in childhood (SUDC) is similar but affects mostly toddlers aged 1 to 4. SUDC is rarer than SIDS, and although cardiogenetic testing (molecular autopsy) identifies an underlying cause in a fraction of SIDS, less is known about SUDC. Methods and Results Seventy-seven SIDS and 16 SUDC cases underwent molecular autopsy with 25 definitive-evidence arrhythmia-associated genes. In 18 cases, another 76 genes with varying degrees of evidence were analyzed. Parents were offered cascade screening. Double-blind review of clinical-genetic data established genotype-phenotype correlations. The yield of likely pathogenic variants in the 25 genes was higher in SUDC than in SIDS (18.8% [3/16] versus 2.6% [2/77], respectively; P=0.03), whereas novel/ultra-rare variants of uncertain significance were comparably represented. Rare variants of uncertain significance and likely benign variants were found only in SIDS. In cases with expanded analyses, likely pathogenic/likely benign variants stemmed only from definitive-evidence genes, whereas all other genes contributed only variants of uncertain significance. Among 24 parents screened, variant status and phenotype largely agreed, and 3 cases positively correlated for cardiac channelopathies. Genotype-phenotype correlations significantly aided variant adjudication. Conclusions Genetic yield is higher in SUDC than in SIDS although, in both, it is contributed only by definitive-evidence genes. SIDS/SUDC cascade family screening facilitates establishment or dismissal of a diagnosis through definitive variant adjudication indicating that anonymity is no longer justifiable. Channelopathies may underlie a relevant fraction of SUDC. Binary classifications of genetic causality (pathogenic versus benign) could not always be adequate.

Adult cascade screening versus child reverse cascade screening in familial hypercholesterolemia

Adult cascade screening versus child reverse cascade screening in familial hypercholesterolemia

The importance of cascade screening of familial hypercholesterolemia in routine clinical practice

The importance of cascade screening of familial hypercholesterolemia in routine clinical practice

Use of lipid-lowering drugs within a multicenter genetic cascade screening program for familial hypercholesterolemia

Use of lipid-lowering drugs within a multicenter genetic cascade screening program for familial hypercholesterolemia

Novel LDLR Variant in Familial Hypercholesterolemia: NGS-Based Identification, In Silico Characterization, and Pharmacogenetic Insights.

Familial Hypercholesterolemia (FH) is a hereditary condition that causes a rise in blood cholesterol throughout a person's life. FH can result in myocardial infarction and even sudden death if not treated. FH is thought to be caused mainly by variants in the gene for the low-density lipoprotein receptor (LDLR). This study aimed to investigate the genetic variants in FH patients, verify their pathogenicity, and comprehend the relationships between genotype and phenotype. Also, review studies assessed the relationship between the LDLR null variants and the reaction to lipid-lowering therapy. The study utilised high-throughput next-generation sequencing for genetic screening of FH-associated genes and capillary sequencing for cascade screening. Furthermore, bioinformatic analysis was employed to describe the pathogenic effects of the revealed novel variant on the structural features of the corresponding RNA molecule. We studied the clinical signs of hypercholesterolemia in a Saudi family with three generations of FH. We discovered a novel frameshift variant (c.666_670dup, p.(Asp224Alafs*43) in the LDLR and a known single nucleotide variant (c.9835A > G, p.(Ser3279Gly) in the APOB gene. It is thought that the LDLR variant causes a protein to be prematurely truncated, likely through nonsense-mediated protein decay. The LDLR variant is strongly predicted to be pathogenic in accordance with ACMG guidelines and co-segregated with the FH clinical characteristics of the family. This LDLR variant exhibited severe clinical FH phenotypes and was restricted to the LDLR protein's ligand-binding domain. According to computational functional characterization, this LDLR variant was predicted to change the free energy dynamics of the RNA molecule, thereby affecting its stability. This frameshift variant is thought to eliminate important functional domains in LDLR that are required for receptor recycling and LDL particle binding. We provide insight into how FH patients with a null variant in the LDLR gene respond to lipid-lowering therapy. The findings expand the range of FH variants and assist coronary artery disease preventive efforts by improving diagnosis, understanding the genotype-phenotype relationship, prognosis, and personalised therapy for patients with FH.

Lipoprotein(a): a Case for Universal Screening in Youth.

Lipoprotein(a) has emerged as a strong independent risk factor for cardiovascular disease. Targeted screening recommendations for Lp(a) measurement exist for adults and youth known to be at high-risk. However, Lp(a) measurements are not included in universal screening guidelines in the US; hence, most families in the US with high Lp(a) levels who are at risk of future atherosclerotic heart disease, stroke, or aortic stenosis are not recognized. Lp(a) measurement included as part of routine universal lipid screening in youth would identify those children at risk of ASCVD and enable family cascade screening with identification and early intervention for affected family members. Lp(a) levels can be reliably measured in children as young as two years of age. Lp(a) levels are genetically determined. The Lp(a) gene is inherited in a co-dominant fashion. Serum Lp(a) attains adult levels by two years of age and is stable for the lifetime of the individual. Novel therapies that aim to specifically target Lp(a) are in the pipeline, including nucleic acid-based molecules such as antisense oligonucleotides and siRNAs. Inclusion of a single Lp(a) measurement performed as part of routine universal lipid screening in youth (ages 9-11; or at ages 17-21) is feasible and cost effective. Lp(a) screening would identify youth at-risk of ASCVD and enable family cascade screening with identification and early intervention for affected family members.

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.