Cascade Screening Research Articles

Experience with cascade screening: A comprehensive family pedigree analysis of two index patients with Fabry disease.

The wide range of clinical symptoms observed in patients with Fabry disease (FD) often leads to delays in diagnosis and initiation of treatment. Delayed initiation of therapy may result in end-organ damage, such as chronic renal failure, hypertrophic cardiomyopathy, and stroke. Although some tools are available to identify undiagnosed patients, new comprehensive screening methods are needed. In this study, the outcomes of the cascade screening applied to three index cases with FD from 2 familes were investigated. In the pedigree analysis, 280 individuals were included; out of them, 131 individuals underwent genetic testing and cascade screening for FD. During the screening program, a total of 45 individuals were diagnosed, with a diagnostic ratio of 1:15. The average age at diagnosis for all individuals was 30.9 ± 17.7 years, and %25 were pediatric cases (mean age 9.5 ± 5.9 years). Thirty affected relatives were diagnosed from thetwo index cases in Family 1 and 15 individuals were diagnosedfrom one index case in Family 2. There were 13 consanguineous marriages observed among 2 pedigres, in two both spouses were affected, leading to two homozygous affected daughters in one couple. In regions where there is a high prevalence of consanguineous marriages, implementing the cascade screening approach to identify all individuals at risk can be beneficial for patients with FD, specifically women and children.

Understanding genomic medicine for thoracic aortic disease through the lens of induced pluripotent stem cells.

Thoracic aortic disease (TAD) is often silent until a life-threatening complication occurs. However, genetic information can inform both identification and treatment at an early stage. Indeed, a diagnosis is important for personalised surveillance and intervention plans, as well as cascade screening of family members. Currently, only 20% of heritable TAD patients have a causative mutation identified and, consequently, further advances in genetic coverage are required to define the remaining molecular landscape. The rapid expansion of next generation sequencing technologies is providing a huge resource of genetic data, but a critical issue remains in functionally validating these findings. Induced pluripotent stem cells (iPSCs) are patient-derived, reprogrammed cell lines which allow mechanistic insights, complex modelling of genetic disease and a platform to study aortic genetic variants. This review will address the need for iPSCs as a frontline diagnostic tool to evaluate variants identified by genomic discovery studies and explore their evolving role in biological insight through to drug discovery.

Variable clinical expression of a novel FLNC truncating variant in a large family

BackgroundVariants in Filamin-C (FLNC) have been associated with various hereditary cardiomyopathies. Recent literature reports a prevalence of sudden cardiac death (SCD) of 13–25% among carriers of truncating-variants, with mean age of 42±15 years for first SCD event. This study reports two familial cases of SCD and the results of cascade screening of their large family. MethodsMolecular-autopsy of the SCD victims revealed a novel truncating-variant in the FLNC gene (chr 7:128496880 [hg19]; NM_001458.5; c.7467_7474del; p.(Ser2490fs)). We screened thirty-two family members following genetic counseling, and variant carriers underwent a comprehensive workup followed by consultation with a cardiologist with expertise in the genetics of cardiac diseases. ResultsSeventeen variant carriers were identified: ages between 9 and 85 (mean 47±26). Fifteen underwent clinical evaluation. To date, none of the identified carriers has had major adverse events. In evaluated patients, ECG showed right-axis deviation in 60% (n = 9). Holter recorded frequent premature ventricular contractions (PVCs) (991±2030 per 24 h) in 33% (n = 5) with 4 patients having polymorphic PVC morphology. Three carriers had echocardiographic evidence of mild left-ventricular (LV) systolic dysfunction and another with mild LV dilatation. Cardiac magnetic-resonance (CMR) exhibited late‑gadolinium-enhancement in 10 out of 11 exams, mainly in the mid-myocardium and sub-epicardium, frequently involving the septum and the inferior-lateral wall. ConclusionThis large FLNC truncating variant carrier family exhibits high cardiomyopathy penetrance, best diagnosed by CMR, with variable clinical expressions. These findings present a challenge in SCD prevention management and underscoring the imperative for better risk stratification measures.

FMO-guided design of darunavir analogs as HIV-1 protease inhibitors

The prevalence of HIV-1 infection continues to pose a significant global public health issue, highlighting the need for antiretroviral drugs that target viral proteins to reduce viral replication. One such target is HIV-1 protease (PR), responsible for cleaving viral polyproteins, leading to the maturation of viral proteins. While darunavir (DRV) is a potent HIV-1 PR inhibitor, drug resistance can arise due to mutations in HIV-1 PR. To address this issue, we developed a novel approach using the fragment molecular orbital (FMO) method and structure-based drug design to create DRV analogs. Using combinatorial programming, we generated novel analogs freely accessible via an on-the-cloud mode implemented in Google Colab, Combined Analog generator Tool (CAT). The designed analogs underwent cascade screening through molecular docking with HIV-1 PR wild-type and major mutations at the active site. Molecular dynamics (MD) simulations confirmed the assess ligand binding and susceptibility of screened designed analogs. Our findings indicate that the three designed analogs guided by FMO, 19–0–14–3, 19–8–10–0, and 19–8–14–3, are superior to DRV and have the potential to serve as efficient PR inhibitors. These findings demonstrate the effectiveness of our approach and its potential to be used in further studies for developing new antiretroviral drugs.

Hypercholesterolemia Familial: Early Cardiovascular Complications, Treatment Challenges, and the Fatal Consequences of Delayed Diagnosis: an in-Depth Case Study

Familial Hypercholesterolemia (FH) is among the most common genetic disorders, present from birth. The transmission is mainly autosomal dominant. It is characterized by a exclusive increase in low-density lipoproteins (LDL). It is associated with a high risk of premature cardiovascular complications. The diagnosis of FH is generally based on the clinical presentation or genetic tests. The commonly used criteria are those of the Dutch Lipid Clinic Network. FH is a hereditary condition still largely underdiagnosed and undertreated. The prognosis of the disease is related to atheromatous cardiovascular complications, which, in the absence of treatment, lead to the patient's death in the first three decades, often due to myocardial infarction or sudden death. The management of familial hypercholesterolemia systematically involves two categories of measures: so-called hygienic-dietary measures associated with the treatment of other risk factors when they exist, and drug treatments. Familial hypercholesterolemia is still poorly detected. It is necessary to develop systematic approaches to identify patients with FH, conduct cascade screening of their relatives, and increase awareness and control of FH.

Cancer Metastasis-on-a-Chip for Modeling Metastatic Cascade and Drug Screening.

Microfluidic chips are valuable tools for studying intricate cellular and cell-microenvironment interactions. Traditional in vitro cancer models lack accuracy in mimicking the complexities of in vivo tumor microenvironment. However, cancer-metastasis-on-a-chip (CMoC) models combine the advantages of 3D cultures and microfluidic technology, serving as powerful platforms for exploring cancer mechanisms and facilitating drug screening. These chips are able to compartmentalize the metastatic cascade, deepening the understanding of its underlying mechanisms. This article provides an overview of current CMoC models, focusing on distinctive models that simulate invasion, intravasation, circulation, extravasation, and colonization, and their applications in drug screening. Furthermore, challenges faced by CMoC and microfluidic technologies are discussed, while exploring promising future directions in cancer research. The ongoing development and integration of these models into cancer studies are expected to drive transformative advancements in the field.

The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young

BackgroundSudden unexpected death in children is a tragic event. Understanding the genetics of sudden death in the young (SDY) enables family counseling and cascade screening. The objective of this study was to characterize genetic variation in an SDY cohort using whole genome sequencing.MethodsThe SDY Case Registry is a National Institutes of Health/Centers for Disease Control and Prevention surveillance effort to discern the prevalence, causes, and risk factors for SDY. The SDY Case Registry prospectively collected clinical data and DNA biospecimens from SDY cases < 20 years of age. SDY cases were collected from medical examiner and coroner offices spanning 13 US jurisdictions from 2015 to 2019. The cohort included 211 children (median age 0.33 year; range 0–20 years), determined to have died suddenly and unexpectedly and from whom DNA biospecimens for DNA extractions and next-of-kin consent were ascertained. A control cohort consisted of 211 randomly sampled, sex- and ancestry-matched individuals from the 1000 Genomes Project. Genetic variation was evaluated in epilepsy, cardiomyopathy, and arrhythmia genes in the SDY and control cohorts. American College of Medical Genetics/Genomics guidelines were used to classify variants as pathogenic or likely pathogenic. Additionally, pathogenic and likely pathogenic genetic variation was identified using a Bayesian-based artificial intelligence (AI) tool.ResultsThe SDY cohort was 43% European, 29% African, 3% Asian, 16% Hispanic, and 9% with mixed ancestries and 39% female. Six percent of the cohort was found to harbor a pathogenic or likely pathogenic genetic variant in an epilepsy, cardiomyopathy, or arrhythmia gene. The genomes of SDY cases, but not controls, were enriched for rare, potentially damaging variants in epilepsy, cardiomyopathy, and arrhythmia-related genes. A greater number of rare epilepsy genetic variants correlated with younger age at death.ConclusionsWhile damaging cardiomyopathy and arrhythmia genes are recognized contributors to SDY, we also observed an enrichment in epilepsy-related genes in the SDY cohort and a correlation between rare epilepsy variation and younger age at death. These findings emphasize the importance of considering epilepsy genes when evaluating SDY.

ACCESS: an empirically-based framework developed by the International Nursing CASCADE Consortium to address genomic disparities through the nursing workforce.

Introduction: Efforts are needed across disciplines to close disparities in genomic healthcare. Nurses are the most numerous trained healthcare professionals worldwide and can play a key role in addressing disparities across the continuum of care. ACCESS is an empirically-based theoretical framework to guide clinical practice in order to ameliorate genomic disparities. Methods: The framework was developed by the International Nursing CASCADE Consortium based on evidence collected between 2005 and 2023 from individuals and families of various ethnic backgrounds, with diverse hereditary conditions, and in different healthcare systems, i.e., Israel, Korea, Switzerland, and several U.S. States. The components of the framework were validated against published scientific literature. Results: ACCESS stands for Advocating, Coping, Communication, cascadE Screening, and Surveillance. Each component is demonstrated in concrete examples of clinical practice within the scope of the nursing profession related to genomic healthcare. Key outcomes include advocacy, active coping, intrafamilial communication, cascade screening, and lifelong surveillance. Advocacy entails timely identification of at-risk individuals, facilitating referrals to specialized services, and informed decision-making for testing. Active coping enhances lifelong adaptation and management of disease risk. Effective intrafamilial communication of predisposition to hereditary disease supports cascade testing of unaffected at-risk relatives. Lifelong surveillance is essential for identifying recurrence, changes in health status, and disease trajectory for life-threatening and for life-altering conditions. Discussion: ACCESS provides a standardized, systematic, situational, and unifying guide to practice and is applicable for nursing and for other healthcare professions. When appropriately enacted it will contribute towards equitable access to genomic resources and services.

Comparison of Two Strategies for Hypercholesterolemia Detection through Point-of-Care Testing.

Childhood dyslipidemia is a common condition that can lead to atherosclerotic cardiovascular disease in adulthood. It is usually multifactorial. Screening for cholesterol disorders in children varies based on risk factors, with some guidelines recommending cascade screening for children with a clear family history of familial hypercholesterolemia, targeted screening for those with specific risk factors, and universal screening. Point-of-care testing (POCT) cholesterol tests offer potential advantages, including ease of use, portability, increased patient access, low cost, fewer medical or laboratory visits, and instant results. This study aimed to evaluate the effect of POCT cholesterol screening on the diagnosis of hypercholesterolemia in children in a family practice setting. We used a POCT cholesterol analyzer to perform two different (universal and targeted) screening approaches for dyslipidemia in children. We used the NCEP guidelines for the classification of the results. We screened 183 children, 105 in the universal screening group and 78 in the targeted screening group. Eight patients in the targeted screening group had elevated cholesterol levels (p = 0.02). All participants received instant feedback and recommendations. Using a targeted screening approach, POCT could be a practical and effective tool for identifying at-risk children with hypercholesterolemia.

Association of Clinical Characteristics With Familial Hypercholesterolaemia Variants in a Lipid Clinic Setting: A Case-Control Study.

Familial hypercholesterolaemia (FH) variant positive subjects have over double the cardiovascular risk of low-density-lipoprotein-cholesterol (LDL-C) matched controls. It is desirable to optimise FH variant detection. We identified 213 subjects with FH gene panel reports (LDLR, APOB, PCSK9, and APOE) based on total cholesterol >310 mg/dL; excluding triglycerides >400 mg/dL, cascade screening, and patients without pre-treatment LDL-C recorded. Demographic, clinical and lipid parameters were recorded. A 31/213 (14.6%) patients had pathogenic or likely pathogenic FH variants. 10/213 (4.7%) had variants of uncertain significance. Compared with patients without FH variants, patients with FH variants were younger (median age, 39 years vs. 48 years), had more tendon xanthomata (25.0% vs. 11.4%), greater proportion of first degree relatives with total cholesterol >95th percentile (40.6% vs. 16.5%), higher LDL-C (median, 271 mg/dL vs. 236 mg/dL), and lower triglycerides (median, 115 mg/dL vs. 159 mg/dL). The Besseling et al. model (c-statistic 0.798) improved FH variant discrimination over Friedewald LDL-C (c-statistic 0.724), however, Dutch Lipid Clinic Network Score (DLCNS) did not (c-statistic 0.665). Sampson LDL-C (c-statistic 0.734) had similar discrimination to Friedewald. Although tendon xanthomata and first degree relatives with high total cholesterol >95th percentile were associated with FH variants, DLCNS or Simon Broome criteria did not improve FH detection over LDL-C. Sampson LDL-C did not significantly improve discrimination over Friedewald. Although lower triglycerides and younger age of presentation are positively associated with presence of FH variants, this information is not commonly used in FH detection algorithms apart from Besseling et al.

Diverse Phenotypic Manifestations in a Family with a Novel RYR2 E4107A Variant.

Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Conversely, RyR2 loss-of-function mutations cause a new disease entity, termed calcium release deficiency syndrome (CRDS), which may include RYR2-related long QT syndrome (LQTS). Importantly, unlike CPVT, patients with CRDS do not always exhibit exercise- or epinephrine-induced ventricular arrhythmias, which precludes a diagnosis of CRDS. Here we report a boy and his father, who both experienced exercise-induced cardiac events and harbor the same RYR2 E4107A variant. In the boy, an exercise stress test (EST) and epinephrine provocation test (EPT) did not induce any ventricular arrhythmias. QTc was slightly prolonged (QTc: 474 ms), and an EPT induced QTc prolongation (QTc-baseline: 466 ms, peak: 532 ms, steady-state: 527 ms). In contrast, in his father, QTc was not prolonged (QTc: 417 ms), and neither an EST nor EPT induced QTc prolongation. However, an EST induced multifocal premature ventricular contraction (PVC) bigeminy and bidirectional PVC couplets. Thus, they exhibited distinct clinical phenotypes: the boy exhibited LQTS (or CRDS) phenotype, whereas his father exhibited CPVT phenotype. These findings suggest that, in addition to the altered RyR2 function, other unidentified factors, such as other genetic, epigenetic, and environmental factors, and aging, may be involved in the diverse phenotypic manifestations. Considering that a single RYR2 variant can cause both CPVT and LQTS (or CRDS) phenotypes, in cascade screening of patients with CPVT and CRDS, an EST and EPT are not sufficient and genetic analysis is required to identify individuals who are at increased risk for life-threatening arrhythmias.

Enhancing Familial Hypercholesterolemia Detection in South Korea: A Targeted Screening Approach Integrating National Program and Genetic Cascade Screening.

Familial hypercholesterolemia (FH) increases the risk of premature cardiovascular disease through disrupted low-density lipoprotein cholesterol (LDL-C) metabolism. Although FH is a severe condition, it remains widely underdiagnosed, which can be attributed to barriers in genetic testing and a lack of awareness. This study aims to propose and evaluate a targeted screening program for FH in South Korea by integrating the General Health Screening Program (GHSP) with cascade genetic screening. The study included individuals with LDL-C levels ≥190 mg/dL identified during the 2021 GHSP (primary participants). Data on demographics, lifestyle, medical history, and family history were collected through questionnaires. Targeted next-generation sequencing was used to identify pathogenic mutations in the PCSK9, APOB, LDLRAP1, and LDLR genes associated with FH. Pathogenic mutations found in primary participants were confirmed in their relatives (secondary participants) using Sanger sequencing. Participant characteristics were analyzed based on the presence of pathogenic mutations. Among 83 individuals with severe hypercholesterolemia identified through the GHSP, 7 primary participants (8.4%) carried pathogenic mutations in the LDLR and PCSK9 genes. In secondary participants, pathogenic mutations were identified in 61.1% of the relatives of 4 patients with pathogenic mutations. The prevalence of pathogenic mutations was significantly higher in primary participants compared to secondary participants. Integrating community resources with FH screening can enhance the early detection and treatment of FH. By utilizing GHSP data and adding genetic screening, the proposed model provides a strategy to reduce the cardiovascular risks associated with FH, supporting its wider adoption at the national level.

Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype

Familial hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB, and PCSK9 genes. Variants in FH-phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, and ABCG8), polygenic hypercholesterolemia, and hyperlipoprotein (a) [Lp(a)] can also mimic a clinical FH phenotype. We aim to present a new diagnostic tool to unravel the genetic background of clinical FH phenotype. Biochemical and genetic study was performed in 1,005 individuals with clinical diagnosis of FH, referred to the Portuguese FH Study. A next-generation sequencing panel, covering eight genes and eight SNPs to determine LDL-C polygenic risk score and LPA genetic score, was validated, and used in this study. FH was genetically confirmed in 417 index cases: 408 heterozygotes and 9 homozygotes. Cascade screening increased the identification to 1,000 FH individuals, including 11 homozygotes. FH-negative individuals (phenotype positive and genotype negative) have Lp(a) >50 mg/dl (30%), high polygenic risk score (16%), other monogenic lipid metabolism disorders (1%), and heterozygous pathogenic variants in FH-phenocopy genes (2%). Heterozygous variants of uncertain significance were identified in primary genes (12%) and phenocopy genes (7%). Overall, 42% of our cohort was genetically confirmed with FH. In the remaining individuals, other causes for high LDL-C were identified in 68%. Hyper-Lp(a) or polygenic hypercholesterolemia may be the cause of the clinical FH phenotype in almost half of FH-negative individuals. A small part has pathogenic variants in ABCG5/ABCG8 in heterozygosity that can cause hypercholesterolemia and should be further investigated. This extended next-generation sequencing panel identifies individuals with FH and FH-phenocopies, allowing to personalize each person’s treatment according to the affected pathway.

Lipoprotein(a): An important piece of the ASCVD risk factor puzzle across diverse populations

Elevated lipoprotein(a) (Lp[a]) is an independent, genetic risk factor for atherosclerotic cardiovascular disease (ASCVD) that impacts ~1.4 billion people globally. Generally, Lp(a) levels remain stable over time; thus, most individuals need only undergo Lp(a) testing through a non-fasting blood draw once in their lifetime, unless elevated Lp(a) is identified. Despite the convenience of the test for clinicians and patients, routine Lp(a) testing has not been widely adopted. This review provides a guide to the benefits of Lp(a) testing and solutions for overcoming common barriers in practice, including access to testing and lack of awareness. Lp(a) testing provides the opportunity to reclassify ASCVD risk and drive intensive cardiovascular risk factor management in individuals with elevated Lp(a), and to identify patients potentially less likely to respond to statins. Moreover, cascade screening can help to identify elevated Lp(a) in relatives of individuals with a personal or family history of premature ASCVD. Overall, given the profound impact of elevated Lp(a) on cardiovascular risk, Lp(a) testing should be an essential component of risk assessment by primary and specialty care providers.

Cascade testing of children and adolescents for elevated Lp(a) in pedigrees with familial hypercholesterolaemia

Elevated plasma lipoprotein(a) [Lp(a)] is a common, inherited condition independently causing cardiovascular disease. Recent expert recommendations suggest opportunistically testing for elevated Lp(a) during cascade testing for familial hypercholesterolaemia (FH). We investigated the effectiveness of detecting elevated Lp(a) in 103 children and adolescents who were first-degree relatives of 66 adult index FH cases as part of an established FH cascade screening program. The yield of detection of elevated Lp(a) using a threshold of ≥30 mg/dL in children and adolescents was assessed. Cascade testing from FH index cases with elevated Lp(a) ≥50 mg/dL identified 1 case of Lp(a) ≥30 mg/dL for every 2 children or adolescents tested. In contrast, opportunistic screening from index cases with FH but normal Lp(a) levels demonstrated 1 case of Lp(a) ≥30 mg/dL for every 7.5 children or adolescents tested (p < 0.001). In conclusion, cascade testing for elevated Lp(a) from index cases with FH and elevated Lp(a) is effective in identifying new cases of elevated Lp(a).

Challenges and Applications of Genetic Testing in Dilated Cardiomyopathy: Genotype, Phenotype and Clinical Implications.

Genetic tests for dilated cardiomyopathy (DCM) have a diagnostic yield of up to 40%, but there is significant genetic heterogeneity and other challenges, such as variable expressivity and incomplete penetrance. Pedigree analysis is essential for distinguishing between sporadic and familial DCM cases by assessing family history. Familial DCM yields higher results in genetic testing, but sporadic DCM does not rule out the possibility of a genetic cause. Some genes have specific phenotypes, with the Lamin gene ( LMNA ) being associated with a phenotype of malignant arrhythmias and advanced heart failure (HF). The presence of a causal genetic variant can also aid in prognostic evaluation, identifying more severe cases with lower rates of reverse remodeling (RR) compared to individuals with a negative genotype. Current guidelines recommend genetic evaluation and counseling for individuals with DCM, along with cascade screening in first-degree relatives in cases where one or more variants are identified, offering an opportunity for early diagnosis and treatment. Relatives with a positive genotype and negative phenotype are candidates for serial evaluation, with frequency varying by age. Genotype also assists in individualized recommendations for implantable cardioverter-defibrillator (ICD) placement and advice regarding physical activity and family planning. Ongoing studies are progressively elucidating the details of genotype/phenotype relationships for a large number of variants, making molecular genetics increasingly integrated into 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.

Genetic testing in presumed cardiac sarcoidosis

Abstract Background Cardiac sarcoidosis (CS) is a difficult to diagnose inflammatory heart disease. Certain types of genetic cardiomyopathy have been reported to masquerade as inflammatory cardiomyopathy. The utility of genetic testing in the evaluation of inflammatory cardiomyopathy is not completely explored and data regarding the prevalence of genetic cardiomyopathies in patients with presumed CS is limited. Methods We retrospectively analyzed patients evaluated from May 2020 to October 2022 in our Cardiac Sarcoid Clinic diagnosed with presumed CS as inferred by either fluorodeoxyglucose positron emission tomography (FDG-PET) - computed tomography (CT) or cardiac magnetic resonance (CMR) or both. Pertinent demographic, genetic, electrocardiographic, and imaging data for these patients was extracted from the electronic medical record. Results Genetic testing was obtained in 47 (22%) of the 213 presumed CS patients, among whom 43 (91%) presented with suspected isolated CS, and 4 (9%) with possible cardiac involvement in the setting of systemic sarcoidosis. Among the patients who underwent genetic testing, 10 (21 %) had a pathogenic or likely pathogenic (P/LP) variant(s) in a genetic cardiomyopathy-susceptibility gene, including DSP (n=2), LMNA, FHL1, TPM1, MYBPC3, NRAS, MYH7 (n=2) and TTN (n= 2) genes. All P/LP patients had FDG uptake, and in those with CMR data, 100% had late gadolinium enhancement. The seven patients with P/LP who underwent endomyocardial biopsy had no evidence of granulomatous inflammation. Immunosuppression was initiated in 60% of the P/LP patients before knowledge of genetic results. Conclusion Patients suspected to have CS may have concomitant or primarily genetic cardiomyopathy that may masquerade as an inflammatory phenotype Genetic testing should be considered in these patients, not only to clarify the diagnosis and its prognostic and therapeutic implications, but also to offer cascade screening for the family of patients with P/LP variants who otherwise would not have been considered to have a heritable disease.

Family screening in hypertrophic cardiomyopathy - clinical and genetic yield at baseline

Abstract Background Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder, often with monogenic inheritance and accordingly, familial aggregation of HCM is common. International guidelines recommend family screening of relatives of patients with HCM to allow pre-symptomatic identification and early interventions. The clinical and genetic yield of implemented screening programs have been scarcely described and might improve by adjustments. We hypothesized that screening can be improved. Purpose To assess the yield of clinical and genetic family screening in HCM at first screening visit. Methods The study was a retrospective study of clinical and genetic cascade screening of adult relatives (age ≥18 years) of HCM probands, screened for familial occurrence of HCM from 2006 to 2022 at a regional assembly of clinics for inherited cardiac diseases (population 2.6 million). We collected demographic, clinical, symptomatic, and genetic characteristics from electronic health records, and a national pedigree database. Diagnostic work-up included a 12-lead ECG, and echocardiography. Relatives of probands carrying a likely pathogenic (LP) or pathogenic (P) variant were also offered cascade genetic testing. Patients and relatives were diagnosed according to the 2014 ESC guidelines. Results We included 603 adult relatives (55% female, mean age 44±15 years) (table 1). At baseline, 118 relatives (20%) fulfilled diagnostic criteria for HCM, and 135 (22%) were carriers of LP/P variants; 78 (13%) of these did not fulfill diagnostic criteria for HCM. Thus, the combined clinical and genetic yield of baseline screening was 33%. A total of 108 (18%) clinically unaffected relatives did not carry the family’s LP/P variant and were discharged from follow-up. This indicates that 50% of the relatives at baseline could be categorized as affected, genetically predisposed or clinically and genetically not at risk. Relatives fulfilling criteria for HCM at baseline were older (51 vs. 42 years, p&amp;lt;0.001), more likely to report cardiopulmonary symptoms (46% vs 16%, p&amp;lt;0.001), be male (59% vs 41%, p&amp;lt;0.001), and have abnormal ECG features (40% vs. 12%, p&amp;lt;0.001), compared to relatives not fulfilling criteria for HCM at baseline. On echocardiography, relatives fulfilling criteria for HCM had a mean maximal wall thickness of 17±4 mm and 14% had left ventricular outflow tract obstruction (gradient at rest/Valsalva≥30 mmHg). Conclusion At baseline screening, one in three relatives of HCM patients were diagnosed with HCM or found to be genetically predisposed to the disease. One in five clinically unaffected relatives not carrying the proband’s disease-causing variant could be discharged from screening. Considering the pattern of inheritance in HCM, the theoretical risk of developing HCM in the remaining 50% of the relatives is low. The non-diagnostic findings may be useful for identification of the remaining truly at-risk relatives.Table 1:Baseline characteristics

Abstract 13421: Meta-Analysis of Penetrance in Genetic Hypertrophic Cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) is clasically caused by pathogenic or likely pathogenic (P/LP) variants in genes encoding sarcomeric proteins (G+) leading to left ventricular hypertrophy (LVH). Aim: To contrast cross-sectional penetrance in clinical and population studies, and to determine the phenotypic conversion (% of G+ developing LVH during follow-up) in longitudinal studies ( Figure 1 ). Methods: A systematic literature search was performed. Pooled penetrance (with 95% confidence intervals [CIs]) and phenotypic conversion were calculated with random effects generalized linear mixed model meta-analyses. Calculations were made for each gene and across all genes. Meta-regression was employed to explore sex-related differences. Results: In cross-sectional clinical studies, after excluding probands, penetrance across all genes in relatives carrying P/LP variants identified during cascade screening was 58% (95% CI [53,64]). Penetrance varied from ~32% for myosin light chain 3 to ~65% for myosin heavy chain 7 ( MYH7 ) and troponin T ( TNNT2 ). The mean age of HCM onset was 38 years (95% CI [36, 40]) across all genes, but studies including a higher % of males reported a later age of onset. In contrast, penetrance in population studies was ~10-15%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in the UK Biobank. In longitudinal clinical studies, the pooled phenotypic conversion was 15% (95% CI [8,27]) over an average of ~7 years of follow up, starting from a mean age of ~16 years across all genes. However, it varied from ~12% for myosin binding protein C to ~23% for MYH7 . Conclusions: The penetrance is 5-7-fold higher in a clinical context compared to incidental identification in population studies, suggesting important but currently undefined factors that modify disease expression. More longitudinal studies are needed to improve understanding of penetrance and identify drivers of the transition from genetic susceptibility to overt HCM