Family Cascade Screening Research Articles

A qualitative study of perceptions of the care pathway for familial hypercholesterolemia: screening, diagnosis, treatment, and family cascade screening

BackgroundFamilial hypercholesterolemia (FH) is an autosomal dominant genetic condition that carries increased risk for premature atherosclerotic cardiovascular disease, cardiovascular events, and death. Due to low uptake of evidence-based practices, up to 80% of FH patients remain undiagnosed and most are undertreated. This project aimed to understand patient and clinician perceptions across the care pathway of evidence-based diagnosis and treatment of FH, to inform implementation strategy design for two clinical trials seeking to increase evidence-based care.MethodsWith input from FH experts, we identified key points along the FH care pathway that might be targeted with broad-scale implementation efforts, including: (a) identification of the need for screening; (b) completion of screening test(s); (c) diagnosis; (d) connection to treatment; and (e) family cascade screening (a process used to identify and screen relatives of individuals diagnosed with FH). Then, we conducted qualitative interviews with patients who had participated in a prior FH quality improvement initiative and with clinicians who treat high cholesterol. We analyzed data using thematic analysis.ResultsWe interviewed 21 patients and 17 clinicians. Patient themes offered insights related to the impact of family history, reactions to a diagnosis of high cholesterol and/or FH, experiences with FH treatment and clinical care, perceptions of tools to diagnose FH, motivations and preferences for FH screening efforts, and reactions to family screening. Clinician themes offered insights into the perceived value of FH screening and diagnosis, current FH-related practice and context, and attitudes toward tools to aid clinical practice. In both sets of interviews, confusion and misconceptions about what makes FH unique and its clinical implications were common, as were concerns about logistics and competing priorities.ConclusionQualitative inquiry generated insights into several modifiable patient and clinician determinants of engagement with evidence-based implementation along the FH care pathway, many of which can be targeted with behavioral economics strategies that simplify complex decisions and by addressing informational and emotional needs. These findings offer actionable insights to inform future implementation research that seeks to close the evidence-to-practice gap in diagnosis and delivery of evidence-based care for FH.

Patient-derived induced pluripotent stem cells to study non-canonical splicing variants associated with Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiomyopathy and a leading cause of sudden death. Genetic testing and familial cascade screening play a pivotal role in the clinical management of HCM patients. However, conventional genetic tests primarily focus on the detection of exonic and canonical splice site variation. Oversighting intronic non-canonical splicing variants potentially contributes to a proportion of HCM patients remaining genetically undiagnosed. Here, using a non-integrative reprogramming strategy, we generated induced pluripotent stem cell (iPSC) lines from four individuals carrying one of two variants within intronic regions of MYBPC3: c.1224-52G > A and c.1898-23A > G. Upon differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), mis-spliced mRNAs were identified in cells harbouring these variants. Both abnormal mRNAs contained a premature termination codon (PTC), fitting the criteria for activation of nonsense mediated decay (NMD). However, the c.1898-23A > G transcripts escaped this mRNA quality control mechanism, while the c.1224-52G > A transcripts were degraded. The newly generated iPSC lines represent valuable tools for studying the functional consequences of intronic variation and for translational research aimed at reversing splicing abnormalities to prevent disease progression.

Uplift of genetic diagnosis of rare respiratory disease using airway epithelium transcriptome analysis.

Rare genetic respiratory disease has an incidence rate of more than 1:2500 live births in Northern Europe and carries significant disease burden. Early diagnosis improves outcomes, but many individuals remain without a confident genetic diagnosis. Improved and expanded molecular testing methods are required to improve genetic diagnosis rates and thereby improve clinical outcomes. Using primary ciliary dyskinesia (PCD) as an exemplar rare genetic respiratory disease, we developed a standardized method to identify pathogenic variants using whole transcriptome RNA-sequencing (RNA-seq) of nasal epithelial cells cultured at air-liquid interface (ALI). The method was optimized using cells from healthy volunteers, and people with rhino-pulmonary disease but no diagnostic indication of PCD. We validated the method using nasal epithelial cells from PCD patients with known genetic cause. We then assessed the ability of RNA-seq to identify pathogenic variants and the disease mechanism in PCD likely patients but in whom DNA genetic testing was inconclusive. The majority of 49 targeted PCD genes were optimally identified in RNA-seq data from nasal epithelial cells grown for 21days at ALI culture. Four PCD-likely patients without a previous genetic diagnosis received a confirmed genetic diagnosis from the findings of the RNA-seq data. We demonstrate the clinical potential of RNA-seq of nasal epithelial cells to identify variants in individuals with genetically unsolved PCD. This uplifted genetic diagnosis should improve genetic counselling, enables family cascade screening, opens the door to potential personalised treatment and care approaches. This methodology could be implemented in other rare lung diseases such as cystic fibrosis.

Whole-exome sequencing to identify causative variants in juvenile sudden cardiac death

BackgroundJuvenile sudden cardiac death (SCD) remains unexplained in approximately 40% of cases, leading to a significant emotional burden for the victims’ families and society. Comprehensive investigations are essential to uncover its elusive causes and enable cascade family screening. This study aimed to enhance the identification of likely causative variants in juvenile SCD cases (age ≤ 50 years), particularly when autopsy findings are inconclusive.ResultsAutopsy revealed diagnostic structural abnormalities in 46%, non-diagnostic findings in 23%, and structurally normal hearts in 31% of cases. Whole-exome sequencing (WES), refined through a customized virtual gene panel was used to identify variants. These variants were then evaluated using a multidisciplinary approach and a structured variant prioritization scheme. Our extended approach identified likely causative variants in 69% of cases, outperforming the diagnostic yields of both the cardio panel and standard susceptibility gene analysis (50% and 16%, respectively). The extended cardio panel achieved an 80% diagnostic yield in cases with structurally normal hearts, demonstrating its efficacy in challenging scenarios. Notably, half of the positive cases harboured a single variant, while the remainder had two or more variants.ConclusionThis study highlights the efficacy of a multidisciplinary approach employing WES and a tailored virtual gene panel to elucidate the aetiology of juvenile SCD. The findings support the expansion of genetic testing using tailored gene panels and prioritization schemes as part of routine autopsy evaluations to improve the identification of causative variants and potentially facilitate early diagnosis in first-degree relatives.

Effectiveness of cascade screening for elevated lipoprotein(a), an underdiagnosed family disorder.

Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent, genetic risk factor for cardiovascular disease. Though crucial for adequate risk assessment, detection of individuals at increased risk because of elevated Lp(a) is severely lacking in practice. In this light, several consensus statements have recommended familial cascade screening strategies to increase detection of elevated Lp(a). This review aims to synthesize findings from recent research into the effectiveness of cascade screening for elevated Lp(a). Cascade screening is an effective method for identifying individuals with elevated Lp(a) and is superior to opportunistic screening. Cascade screening identifies approximately one new case of elevated Lp(a) ≥ 125 nmol/L for every two first-degree relatives screened. The number needed to screen (NNS) ranged from 1.3 to 2.9, depending on Lp(a) threshold values and selected population. Cascade screening appears to be a promising strategy for identifying individuals with elevated Lp(a). However, several challenges persist regarding the implementation of this strategy in clinical practice. Deciding on threshold values for initiating cascade screening, considering the implications of ethnicity-related variability of Lp(a) levels, and further research into the clinical relevance of cascade screening are crucial steps. Understanding these factors will be essential for optimizing cascade screening protocols and enhancing its effectiveness in clinical practice.

Molecular genetics in 1991 arrhythmia probands and 2782 relatives in Norway: Results from 17 years of genetic testing in a national laboratory.

The aim of this study was to explore the prevalence of likely pathogenic or pathogenic variants and assess the diagnostic yield from genetic testing for cardiac arrhythmias in Norway since 2003. Data from 1991 probands and 2782 relatives were retrospectively collected from the laboratory information management system at Unit for Cardiac and Cardiovascular Genetics, Oslo University hospital. Of 1991 probands, 57.4% were females, age at genetic testing was 33.1 (±22.7) years, and 32.5% were under the age of 18. A likely pathogenic or pathogenic variant (including 14 novel) was detected in 15.4% in total. Of the 2782 relatives, 53.7% were females, age at genetic testing was 35.6 (±22.5) years, 27.3% were under the age of 18, and 45.3% carried the family variant. Probands and relatives combined, 1/3356 persons in the Norwegian population were heterozygous for an arrhythmia-causing variant. The founder variant p.Q530X (NM_000218.2: c.1588C>T) in KCNQ1 accounted for 34% of all variants in Norway. In conclusion, genetic testing provided a genetic basis of the arrhythmia in 15.4% of the probands. Familial cascade screening identified four times as many variant-positive relatives, allowing early detection and prompt stratification of arrhythmic risk of those variant carriers.

Molecular autopsy in Chinese sudden cardiac death in the young.

Inherited cardiovascular conditions are significant causes of sudden cardiac death in the young (SCDY), making their investigation using molecular autopsy and prevention a public health priority. However, the molecular autopsy data in Chinese population is lacking. The 5-year result (2017-2021) of molecular autopsy services provided for victims of SCDY (age 1-40 years) was reviewed. The outcome of family cascade genetic screening and clinical evaluation was reviewed. A literature review of case series reporting results of molecular autopsy on SCDY in 2016-2023 was conducted. Among the 41 decedents, 11 were found to carry 13 sudden cardiac death (SCD)-causative genetic variants. Likely pathogenic (LP) variants were identified in the DSP, TPM1, TTN, and SCN5A genes. Cascade genetic testing identified four family members with LP variants. One family member with familial TPM1 variant was found to have hypertrophic cardiomyopathy upon clinical evaluation. This study provided insight into the genetic profile of molecular autopsy in a Chinese cohort of SCDY. The detection of important SCD-causative variants through molecular autopsy has facilitated family cascade screening by targeted genetic testing and clinical evaluation of at-risk family members. A literature review of the current landscape of molecular autopsy in the investigation of SCDY was conducted.

Prevention of life threating arrythmias in relatives of cardiac arrest survivors; results of family cascade screening in a representative cohort in Czech Republic

Prevention of life threating arrythmias in relatives of cardiac arrest survivors; results of family cascade screening in a representative cohort in Czech Republic

#1468 Alport syndrome family screening and management—experience of a tertiary center

Abstract Background and Aims Alport syndrome (AS) is the most common cause of inherited chronic kidney disease. This disorder is caused by deleterious variants on COL4A3, COL4A4 or COL4A5 genes. These genes codify the proteins that constitute collagen type IV of the glomerular basement membrane (GBM). Importantly, AS patients can develop chronic kidney disease (CKD) kidney disease that can be delayed or possibly prevented by timely initiation of therapy. The identification of at-risk relatives and their genetic testing allow to identify AS patients and initiate appropriate renal care and avoid unnecessary vigilance if the test is negative. Our aim was to assess the outcomes of Alport Syndrome cascade family screening in a tertiary hospital. Method In this study, we retrospectively assessed familial relatives at risk of AS index cases in our Nephrogenetics consult, from January 2018 to November 2023. After referral, routine tests to detect renal disease were done and AS gene panel was performed. Demographic and clinical data were also compiled. Results A total of 75 at-risk relatives were assessed, belonging to 26 families with a COL4A variant identified in the index case. Relatives at risk were mostly referred by primary care doctors (n = 52, 69.3%), with other 15 patients (20%) directly scheduled for consultation, and 8 (10.7%) referred by a nephrology clinic. In this cohort, an AS diagnosis was confirmed in 43 relatives (57.3%), with an additional 13 (17.3%) of the at-risk relatives with ongoing biochemical or molecular analyses. In 19 (25.4%) relatives the molecular study allowed the exclusion of AS. In the subgroup of patients diagnosed with AS (n = 43): median age at molecular diagnosis was 40.5 years (IQR 20.2-56.5years) and 26 (60.5%) were female. Thirty-five patients (81.4%) patients had autosomal dominant AS: 32 had a variant in COL4A3 (6 different variants were found: 4 were pathogenic or likely pathogenic and 2 were of uncertain significance) and 3 patients on COL4A4. COL4A5 variants were identified in 8 patients, 5 of them were female. Three (7%) patients presented with intermittent hematuria, 14 (32.6%) patients presented isolated hematuria, 10 (23.2%) patients had urinary protein/creatine (Up/cr) <0,3g/g, 7 (16.2%) presented Up/cr between 0.3g/g and 1g/g, 3 (7%) patients had Up/cr >1g/g; Six (14%) had CKD. Twenty-two (51.2%) patients were started on a renin angiotensin system inhibitor (RASi) and 5 (11.6%) were already under a RASi. At the last visit in this group of AS patients, the mean epiTFG was 104.2 ml/min (IQ 85.6-120-5 ml/min) and 6 (14%%) patients had epiTFG below 60 ml/min; mean Uprot/creat was 0.11g/g (IQR 0.06-0.32), 12 (28%) patients had no proteinuria. In the subgroup of relatives at risk were AS excluded (n = 19): median age was 38.5 years (IQR 20.2-56.0) and 11 (58%) were female. One patient had CKD, 7 (36.8%) had no signs of renal disease and 8 (42%) patients had intermittent hematuria. Conclusion Our retrospective review showed that the systematic screening of relatives at risk in our hospital was met with a high discovery rate of AS patients. Since there is clinical benefit in an early AS diagnosis, namely through improved renal care and prevention of disease progression, timely genetic/biochemical screening of at-risk relatives is advisable. Additionally, by discharging the relatives with a negative test, this is a more cost-effective approach than providing continuous vigilance to all.

Family cascade screening for equitable identification of familial hypercholesterolemia: study protocol for a hybrid effectiveness-implementation type III randomized controlled trial

BackgroundFamilial hypercholesterolemia (FH) is a heritable disorder affecting 1.3 million individuals in the USA. Eighty percent of people with FH are undiagnosed, particularly minoritized populations including Black or African American people, Asian or Asian American people, and women across racial groups. Family cascade screening is an evidence-based practice that can increase diagnosis and improve health outcomes but is rarely implemented in routine practice, representing an important care gap. In pilot work, we leveraged best practices from behavioral economics and implementation science—including mixed-methods contextual inquiry with clinicians, patients, and health system constituents—to co-design two patient-facing implementation strategies to address this care gap: (a) an automated health system-mediated strategy and (b) a nonprofit foundation-mediated strategy with contact from a foundation-employed care navigator. This trial will test the comparative effectiveness of these strategies on completion of cascade screening for relatives of individuals with FH, centering equitable reach.MethodsWe will conduct a hybrid effectiveness-implementation type III randomized controlled trial testing the comparative effectiveness of two strategies for implementing cascade screening with 220 individuals with FH (i.e., probands) per arm identified from a large northeastern health system. The primary implementation outcome is reach, or the proportion of probands with at least one first-degree biological relative (parent, sibling, child) in the USA who is screened for FH through the study. Our secondary implementation outcomes include the number of relatives screened and the number of relatives meeting the American Heart Association criteria for FH. Our secondary clinical effectiveness outcome is post-trial proband cholesterol level. We will also use mixed methods to identify implementation strategy mechanisms for implementation strategy effectiveness while centering equity.DiscussionWe will test two patient-facing implementation strategies harnessing insights from behavioral economics that were developed collaboratively with constituents. This trial will improve our understanding of how to implement evidence-based cascade screening for FH, which implementation strategies work, for whom, and why. Learnings from this trial can be used to equitably scale cascade screening programs for FH nationally and inform cascade screening implementation efforts for other genetic disorders.Trial registrationClinicalTrials.gov, NCT05750667. Registered 15 February 2023—retrospectively registered, https://clinicaltrials.gov/study/NCT05750667.

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.

Abstract 14343: Early Genetic Screening and Cardiac Intervention in Patients With Genetic Cardiomyopathies Within a Multidisciplinary Care Model

Introduction: Patients with genetic cardiomyopathies are a heterogeneous group of patients who experience significant morbidity and mortality. Early cardiac assessment and intervention coupled with access to genetic counselling and testing may improve clinical outcomes and prevent progression to end-stage heart failure. Methods: Our prospective cohort study was conducted at our multidisciplinary Cardiomyopathy Clinic and patients with suspected genetic cardiomyopathy (CM) or a family history of CM ( n =405) were recruited. Patients with genetic analysis completed ( n =228) were categorized into dilated cardiomyopathy (DCM) ( n= 118), hypertrophic cardiomyopathy (HCM) ( n= 55), infiltrative cardiomyopathy (CM) ( n= 18), and Stage A/at-risk for CM ( n= 37). Continuous variables were analyzed using Wilcoxon signed-rank test or paired t test, while categorical variables were compared using Pearson chi-square tests. Results: There was a median follow-up time of 13 months (IQR: 7 - 21 months) with an increase in genetic testing, cascade family screening, optimization of guideline-directed medical therapy, and usage of device therapies compared to prior to clinic enrolment. In patients with genetic testing, 29.4% ( n= 67) had positive genotypes (pathogenic or likely pathogenic variants), 11.8% ( n= 27) had variants of unknown significance (VUS), and 58.8% ( n= 134) had negative or inconclusive genotypes. Optimization of medical and device therapies resulted in improvements in left ventricular ejection fraction from 30.5% (20.8 - 42.5%) to 45.5% (34.0 - 48.5%, P&lt; 0.001), reduced left ventricular mass index from 121.2 g/m 2 (116.2 - 146.4 g/m 2 ) to 107.0 g/m 2 (88.9 - 134.7 g/m 2 , P&lt; 0.001), and reduced E/e’ ratio from 12.6 cm/s (9.2 - 15.3 cm/s) to 10.9 cm/s (9.0 - 14.2 cm/s, P= 0.015). These improvements were driven by patients with negative genotypes (no variants or VUS) relative to those with positive genotypes. Additionally, patients with normal blood pressure (SBP &lt; 120 mmHg and DBP &lt; 80 mmHg) at follow-up had improvement in LVEF ( P&lt; 0.001) and LVMI ( P= 0.005). Conclusion: Our findings demonstrate the efficacy of a combined cardiovascular genetics clinic in improving the clinical trajectories of patients with genetic cardiomyopathies.

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 &lt;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) &lt;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.

Differential Diagnosis of Cardiac Amyloidosis and Hypertrophic Cardiomyopathy

Diagnosis and differential diagnosis of cardiac amyloidosis and hypertrophic cardiomyopathy is difficult in some cases, which is confirmed by the presented clinical observation. The patient A., 67 years old, from the age of 59 for 7 years suffered from arterial hypertension with a maximum blood pressure of 170/100 mmHg, received hypotensive therapy. Myocardial infarction, a history of stroke denies. Since January 2018, at the age of 65, against the background of spontaneous stabilization of blood pressure figures, shortness of breath when climbing to the 2nd floor, lifting weights, suffocation at night, swelling of the shins, feet, in connection with which I turned to a doctor. When examined on an electrocardiogram, a low voltage of QRS complexes in the leads from the extremities was noted, there was no increase in the amplitude of the r wave in V1–3. Echocardiography revealed a thickening of the interventricular septum and the posterior wall of the left ventricle up to 1.9 cm without obstruction of the outlet of the left ventricle, restrictive type of diastolic dysfunction, dilation of the left and right atria, moderate pulmonary hypertension, moderate amount of fluid in the pericardial cavity. Magnetic resonance imaging of the heart revealed a pattern typical of cardiac amyloidosis: diffuse subendocardial contrast of the myocardium of both ventricles in the absence of local contractility disorders, increased myocardial thickness in all segments, hydropericardium. Biopsy of the skin and subcutaneous fat with Congo red staining and polarization microscopy revealed no amyloid deposits. No mutations in the transthyretin gene responsible for transthyretin amyloidosis (ATTR–amyloidosis) were detected during the genetic study. Sequencing of 10 genes encoding myocardial sarcomeric proteins in the MYBPC3 gene revealed a mutation c.3197C &gt;G (p.Pro1066Arg) in a heterozygous state, previously described in patients with hypertrophic cardiomyopathy of Slavic origin. Cascade family screening for the mutation was not carried out due to the fact that the patient did not know the father, the mother died at the age of 75 from heart failure, the only son died from an accident six months before the patient’s treatment. On 15.02.2019, the patient suffered a circulatory arrest with successful resuscitation measures. For the purpose of secondary prevention of sudden cardiac death, a single–chamber cardioverter-defibrillator was implanted on 22.02.2019. Despite the ongoing therapy, the patient died in March 2019. from progressive heart failure. Thus, a clinical case is presented where magnetic resonance imaging suspected amyloid cardiomyopathy, which did not receive morphological confirmation in biopsies of extra–cardiac localization. Hypertrophic cardiomyopathy caused by mutation c.3197C &gt;G (p.Pro1066Arg) in the MYBPC3 gene was confirmed on the basis of clinical and instrumental and molecular genetic methods. The pattern characteristic of cardiac amyloidosis described in this patient with instrumental examination methods may be due to a violation of autophagy processes previously described with a number of mutations in the MYBPC3 gene, which may lead to the accumulation of amyloid-like inclusions in cardiomyocytes. For differential diagnosis of cardiomyopathies in complex cases, endomyocardial biopsy may be required. The possibility of coexistence of genetically determined hypertrophic cardiomyopathy and amyloid heart disease is not excluded.

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.

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 spectrum of familial and sporadic dilated cardiomyopathy: arrhythmic phenotypes associated with mutations in the lamin A/C (LMNA) gene

Purpose. To study the diagnostic value of cascade family screening and the spectrum of genetic variants in patients with familial and sporadic DCM, assess clinical outcomes and comparative analysis of 5-year event-free survival.Materials and methods. The study included 156 unrelated patients with verified DCM. All patients (aged 46 [34; 57] years; 125 (80%) male; LVEF 31 [24; 38]%; LV EDD 68 [61; 74] mm; follow-up period - 77 [59; 108] months) a complex of clinical and instrumental studies (ECG, ECHO, HM, MRI), cascade family screening with genetic testing (NGS+Sanger) and segregation analysis were performed.Results. Criteria for familial DCM were identified in 73 (46.8%) probands. The genetic cause of DCM was identified in 47 (64,4%) familial cases, while for sporadic form DCM pathogenic variants were detected in 19 (22,9%) patients. The dominant mutations were truncating variants in the titin gene (10,9%) and variants in the lamin A/C (LMNA) gene - 8,33%. As a result of the evaluation of cumulative event-free survival (Kaplan-Meier curves), LMNA carriers showed the poor 5-year prognosis for ventricular tachyarrhythmic events (x2=39.9; p=0,0001) and composite adverse outcomes (x2=12.1; p=0.001). Probands who had a familial DCM (log rang x2=38.5; p=0,0001) showed the worst prognosis and low cumulative survival when compared with patients of the sporadic DCM.Conclusion. Cascade clinical family screening and genetic testing in the DCM cohort increased the level of diagnosis of familial DCM from 4.5% to 46.8%. Associations of LMNA mutations with life-threatening tachyarrhythmias are defined as prognostically significant, that confirms the important role of genetic stratification of arrhythmic risk.

Tools to differentiate between Filamin C and Titin truncating variant carriers: value of MRI.

Whereas truncating variants of the giant protein Titin (TTNtv) are the main cause of familial dilated cardiomyopathy (DCM), recently Filamin C truncating variants (FLNCtv) were identified as a cause of arrhythmogenic cardiomyopathy (ACM). Our aim was to characterize and compare clinical and MRI features of TTNtv and FLNCtv in the Belgian population. In index patients referred for genetic testing of ACM/DCM, FLNCtv and TTNtv were found in 17 (3.6%) and 33 (12.3%) subjects, respectively. Further family cascade screening yielded 24 and 19 additional truncating variant carriers in FLNC and TTN, respectively. The main phenotype was ACM in FLNCtv carriers whereas TTNtv carriers showed either an ACM or DCM phenotype. Non-sustained Ventricular Tachycardia was frequent in both populations. MRI data, available in 28/40 FLNCtv and 32/52 TTNtv patients, showed lower Left Ventricular (LV) ejection fraction and lower LV strain in TTNtv patients (p < 0.01). Conversely, both the frequency (68% vs 22%) and extent of non-ischemic myocardial late gadolinium enhancement (LGE) was significantly higher in FLNCtv patients (p < 0.01). Hereby, ring-like LGE was found in 16/19 (84%) FLNCtv versus 1/7 (14%) of TTNtv patients (p < 0.01).In conclusion, a large number of FLNCtv and TTNtv patients present with an ACM phenotype but can be separated by cardiac MRI. Whereas FLNCtv patients often have extensive myocardial fibrosis, typically following a ring-like pattern, LV dysfunction without or limited replacement fibrosis is the common TTNtv phenotype.

Rare Compound Heterozygous Missense Mutation of the SCN5A Gene with Childhood-Onset Sick Sinus Syndrome in Two Chinese Sisters.

Sick sinus syndrome (SSS) is a group of syndromes characterized by pathological changes in the sinoatrial node and its adjacent tissues. Although several mutations in the SCN5A gene have been associated with early-onset SSS, pediatric patients are still less common. Here, we report a rare compound missense mutation in the SCN5A gene [c.2893C>T (p. R965C) and c.2431C>T (p. R811C) ] in two sisters with childhood-onset SSS in Chinese population. The proband (5 years and 5 months old) was the second child of a clinically normal and nonconsanguineous couple. Her elder sister was 12 years old and had been implanted with a pacemaker because of the diagnosis of SSS at another hospital one year ago. The proband was presented to the hospital with a slowed heart rate and reduced endurance exercise capacity for more than three months. After a comprehensive clinical examination, she was diagnosed with SSS and underwent pacemaker implantation. Exome and Sanger sequencing were used to determine the compound heterozygous missense mutation of [c.2893C>T (p. R965C) and c.2431C>T (p. R811C) ] in the SCN5A in the patient and her elder sister. Each healthy parent carried a different heterozygous missense mutation. The compound heterozygous mutation of c.2893C>T (p. R965C) and c.2431C>T (p. R811C) rather than the single mutation might be the primary cause of familial early-onset SSS in Chinese population. Our current findings expanded the current understanding of the SCN5A gene mutations. We further confirmed the essential role of the SCN5A gene on the diagnosis, family cascade screening, early intervention, and prognostic evaluation of SSS.