Genetic Causes Of Cardiomyopathies Research Articles

Abstract 18532: Cardiomyopathy Diagnoses in a General Population Study of TTN Pathogenic Variants: A Missed Opportunity to Diagnose Familial Cardiomyopathy?

Introduction: Intermountain Health’s HerediGene Population Study has been collecting samples from over 175,000 individuals since 2018 to identify those that could potentially benefit from early interventions. Variants in the TTN gene are the most common genetic causes of cardiomyopathy (CM). Here we examined all individuals with TTN pathogenic or likely pathogenic variants to determine differences in clinical characteristics among those with and without a clinical CM diagnosis (Dx). Methods: Whole genome sequence was analyzed in 32,159 individuals. 411 (1.3%) had a pathogenic/likely pathogenic TTN variant . Of these 135 (32.8%) had a CM Dx and 276, (67.2%) did not. Differences in health histories, ECHO results, treatments, and major CV events were evaluated by presence or absence of CM Dx using the chi-square, Fisher exact, and Wilcoxon rank sum tests. Results: Demographic and clinical characteristics were significantly different among those with and without a CM Dx (Table). In those without CM Dx, a total of 75 (27%) had some clinical indication of potential CM: 37 having a BNP ≥100, 7 had an LVIDd ≥ 5.5, 33 with an EF ≤55%, 3 experiencing cardiac arrest, and 45 with a heart failure Dx. Of these, 21 (28%) had 2 of these indications, 13 (17%) had 3 indications, and 1 (1%) had 4 indications. Among these with indication of CM without a Dx, 12 (16%) have died, and 22 (23%) have been hospitalized for heart failure. Only 8 individuals had a clinical genetic test for CM with a positive result for TTN variant. Conclusion: About 1/3 of potential pathogenic TTN variant carriers had a CM Dx and 27% without a CM Dx had indication of possible CM. A small percentage of TTN variant carriers with a CM Dx and none of those with possible CM have undergone clinical genetic testing. This demonstrates a missed opportunity to diagnose potential TTN -related familial CM for earlier intervention and treatment of patients and family members.

Morphological and genetic causes of fetal cardiomyopathies.

Cardiomyopathies are diseases of the heart muscle with variable clinical expressivity. Most of forms are inherited as dominant trait, and with incomplete penetrance until adulthood. Severe forms of cardiomyopathies were observed during the antenatal period with a pejorative issue leading to fetal death or medical interruption of pregnancy. Variable phenotypes and genetic heterogeneity make etiologic diagnosis difficult. We report 11 families (16 cases) whose unborn, newborn or infant with early onset cardiomyopathies. Detailed morphological and histological examinations of hearts were implemented, as well as genetic analysis on a cardiac targeted NGS panel. This strategy allowed the identification of the genetic cause of the cardiomyopathy in 8/11 families. Compound heterozygous mutations in dominant adulthood cardiomyopathy genes were found in two, pathogenic variants in co-dominant genes in one, de novo mutations in 5 including a germline mosaicism in one family. Parental testing was systematically performed to detect mutation carriers, and to manage cardiological surveillance and propose a genetic counseling. This study highlights the great diagnostic value of the genetic testing of severe antenatal cardiomyopathy both for genetic counseling and to detect presymptomatic parents at higher risk of developing cardiomyopathy.

Genetic testing and family screening in idiopathic pediatric cardiomyopathy: a prospective observational study from a tertiary care center in North India

IntroductionThere are limited data on family screening and genetic testing in pediatric cardiomyopathy from India. This study was conducted to describe the morphologic spectrum and identify potential familial and genetic causes of pediatric cardiomyopathies in this region.MethodsFrom April 2018 to May 2020, all children from birth to 18 years of age with cardiomyopathy visiting a tertiary care hospital in North India were enrolled in this study. First-degree relatives of index patients were offered screening for cardiomyopathy; 260 clinically reported pathogenic/likely pathogenic variants in 17 genes were analyzed by a rapid genotyping method. Additionally, a subset of patients also underwent whole-exome sequencing.ResultsOf the 20 patients enrolled in this study (median age 42 months), 18 were clinically diagnosed with dilated cardiomyopathy. We observed a 44.4% mortality rate after a median follow-up of 15 months. 61.3% of the eligible first-degree relatives underwent screening, and one patient was identified to have familial cardiomyopathy. Multi-panel gene testing was performed on 18 patients, and none were found to have a pathogenic or likely pathogenic variant; 9 patients also underwent whole-exome sequencing, and pathogenic and likely pathogenic variants were identified in 50% (4/8) of them.ConclusionDilated cardiomyopathy is the most common morphologic form of pediatric cardiomyopathy in India and has a high mortality rate. The prevalence of familial cardiomyopathy was low in this study. Future studies should evaluate the role of whole-exome sequencing in identifying genetic causes of cardiomyopathy in children.

263 GENETIC CAUSES OF CARDIOMYOPATHIES IN CHILDREN

Abstract Background The genetic background of paediatric cardiomyopathies is only partially resolved, because of their rarity and heterogeneity. However, the assessment of aetiology is of paramount importance in order to define prognosis and therapeutic choices. Moreover, the recognition of genetic causes is the basis for cascade screening in the family. Aims This study aimed to identify the genetic causes of cardiomyopathies in children evaluated and followed at our paediatric hospital. Methods A validated Next Generation Sequencing (NGS) target panel was performed in a cohort of 76 paediatric patients: 36 Hypertrophic Cardiomyopathy, (HCM), 24 Dilated Cardiomyopathy (DCM), 3 Restrictive Cardiomyopathy (RCM), 2 Left Ventricular Non Compaction (LVNC), 10 Arrhythmogenic Cardiomyopathy (AC) and one with a cardiac arrest. Genetic counselling was offered to parents. Furthermore, 9 patients with negative genes panel were selected for Whole Exome Sequencing (WES). Results By target genes panel analysis we identified a pathogenic or likely pathogenic variant in 32/76 patients (42%). Most genotyped patients had a sarcomeric aetiology and MYH7 (11/32, 34%), MYBPC3 (7/32, 22%) and thin-filaments genes (9/32, 28%) resulted the most mutated genes. 11/32 (34%) patients had a complex genotype. In one patient we found the rare coexistence of two independent monogenic diseases (Osteogenesis Imperfecta and HCM) due respectively to COL1A1 and MYH7 variants. Moreover, we identified five syndromic cases (5/32, 16%): three patients with Noonan Syndrome (one with SOS1 variant and two with PTPN11 variants), one boy with Danon Disease (with LAMP2 variant) and a newborn with Alström Syndrome (due to ALMS1 variants). By WES we identified a de novo variant in FLNC gene in a 7 years old child RCM, a Noonan Syndrome due to biallelic LZTR1 variants in a 9 years old child, two PLEC1 variants in a newborn with DCM and Epidermolysis bullosa, and a de novo NKX2-5 variant in a child with RCM. Conclusions A definitive molecular diagnosis could be obtained in a substantial proportion of children (42%). The genetic test results had direct implications for clinical management, to suggest therapeutic interventions. Moreover, predictive genetic testing in family members resulted very important for clinical follow-up and to establish the recurrence risk for subsequent pregnancies.

Alcohol Intake in Patients With Cardiomyopathy and Heart Failure: Consensus and Controversy.

Alcohol is often cited to be a common cause of cardiomyopathy and heart failure. However, in most available population-based studies, a modest-to-moderate alcohol consumption has been associated with favorable effects on the cardiovascular system, including a lowered risk of heart failure, compared with no alcohol consumption. Available genetic epidemiological data have not supported a causal association between alcohol consumption and heart failure risk, suggesting that alcohol may not be a common cause of heart failure in the community. Data linking alcohol intake with cardiomyopathy risk are sparse, and the concept of alcoholic cardiomyopathy stems mainly from case series of selected patients with dilated cardiomyopathy, where a large proportion reported a history of excessive alcohol intake. This state-of-the-art paper addresses the current knowledge of the epidemiology of alcoholic cardiomyopathy and the role of alcohol intake in patients with non-alcohol-related heart failure. It also offers directions to future research in the area. The review questions the validity of current clinical teaching in the area. It is not well known how much alcohol is needed to cause disease, and the epidemiological pathways linking alcohol consumption to cardiomyopathy and heart failure are not well understood. Until more evidence becomes available, caution is warranted before labeling patients as having alcoholic cardiomyopathy due to a risk of neglecting other contributors, such as genetic causes of cardiomyopathy. In non-alcohol-related heart failure, it is unknown whether total abstinence is improving outcomes (compared with moderate drinking). Ideally, randomized clinical trials are needed to answer this question.

Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study.

BackgroundPediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices.Methods and ResultsChildren with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (P=0.005 and P=0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes.ConclusionsA definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first‐degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT01873963.

Rationale and design of the African Cardiomyopathy and Myocarditis Registry Program: The IMHOTEP study

BackgroundHeart failure (HF), the dominant form of cardiovascular disease in Africans, is mainly due to hypertension, rheumatic heart disease and cardiomyopathy. Cardiomyopathies pose a great challenge because of poor prognosis and high prevalence in low- and middle-income countries (LMICs). Little is known about the etiology and outcome of cardiomyopathy in Africa. Specifically, the role of myocarditis and the genetic causes of cardiomyopathy are largely unidentified in Africans. MethodThe African Cardiomyopathy and Myocarditis Registry Program (the IMHOTEP study) is a pan-African multi-centre, hospital-based cohort study, designed with the primary aim of describing the clinical characteristics, genetic causes, prevalence, management and outcome of cardiomyopathy and myocarditis in children and adults. The secondary aim is to identify barriers to the implementation of evidence-based care and provide a platform for trials and other intervention studies to reduce morbidity and mortality in cardiomyopathy. The registry consists of a prospective cohort of newly diagnosed (i.e., incident) cases and a retrospective (i.e., prevalent) cohort of existing cases from participating centres. Patients with cardiomyopathy and myocarditis will be subjected to a standardized 3-stage diagnostic process. To date, 750 patients have been recruited into the multi-centre pilot phase of the study. ConclusionThe IMHOTEP study will provide comprehensive and novel data on clinical features, genetic causes, prevalence and outcome of African children and adults with all forms of cardiomyopathy and myocarditis in Africa. Based on these findings, appropriate strategies for management and prevention of the cardiomyopathies in LMICs are likely to emerge.

Genetics of paediatric cardiomyopathies.

Paediatric cardiomyopathy is a rare disease with a genetic basis. The purpose of this review is to discuss the current status of genetic findings in the paediatric cardiomyopathy population and present recent progress in utilizing this information for management and therapy. With increased clinical genetic testing, an understanding of the genetic causes of cardiomyopathy is improving and novel causes are identified at a rapid rate. Recent progress in identifying the scope of genetic variation in large population datasets has led to reassessment and refinement of our understanding of the significance of rare genetic variation. As a result, the stringency of variant interpretation has increased, at times leading to revision of previous mutation results. Transcriptome and epigenome studies are elucidating important pathways for disease progression and highlight similarities and differences in pathogenesis from adult cardiomyopathy. Therapy targeted towards the underlying cause of cardiomyopathy is emerging for a number of rare syndromes such as Pompe and Noonan syndromes, and genome editing and induced pluripotent stem cells provide promise for additional precision medicine approaches. Genetics is moving at a rapid pace in paediatric cardiomyopathy. Genetic testing is increasingly being incorporated into clinical care. Although interpretation of rare genetic variation remains challenging, the opportunity to provide management and therapy targeted towards the underlying genetic cause is beginning to be realized.

Evaluation of genetic causes of cardiomyopathy in childhood.

Cardiomyopathy frequently has a genetic basis. In adults, mutations in genes encoding components of the sarcomere, cytoskeleton, or desmosome are frequent genetic causes of cardiomyopathy. Although children share these causes, ~30% of children have an underlying metabolic, syndromic, or neuromuscular condition causing their cardiomyopathy, making the aetiologies more diverse in children as compared with adults. Although some children present with obvious signs or symptoms of metabolic, syndromic, or neuromuscular disease, other cases may be quite subtle, requiring a high level of suspicion in order to diagnose them. In general, the younger the child, the more extensive the differential. Advantages of identifying the underlying genetic cause of cardiomyopathy in the paediatric population include confirming the diagnosis in ambiguous cases, facilitating appropriate surveillance and management of cardiac and extra-cardiac diseases, providing prognostic information, and establishing the genetic basis in the family, thereby allowing the identification of at-risk relatives and institution of appropriate family screening as indicated. For these reasons, genetic testing is increasingly recognised as standard of care, and guidelines for genetic counselling, testing, and incorporation of family-based risk assessment have been established. Therapies aimed at treating specific genetic aetiologies of cardiomyopathy are emerging and are exciting new developments that require increasingly sophisticated approaches to diagnosis. As genetic testing capabilities continue to expand technically, careful interpretation, knowledgeable clinical utilisation, and appropriate dissemination of genetic information are important and challenging components of clinical care.

Genetic causes of cardiomyopathies identified by Whole Exome Sequencing

Genetic causes of cardiomyopathies identified by Whole Exome Sequencing

Next-generation sequencing to identify genetic causes of cardiomyopathies

This review examines the application of next-generation sequencing (NGS) technologies in the identification of the causation of nonsyndromic genetic cardiomyopathies. NGS sequencing of the entire genetic coding sequence (the exome) has successfully identified five novel genes and causative variants for cardiomyopathies without previously known cause within the last 12 months. Continual rapidly decreasing costs of NGS will shortly allow cost-effective sequencing of the entire genomes of affected individuals and their relatives to include noncoding and regulatory variant discovery and epigenetic profiling. Despite this rapid technological progress with sequencing, analysis of these large data sets remains challenging, particularly for assigning causality to novel rare variants identified in DNA samples from patients with cardiomyopathy. NGS technologies are rapidly moving to identify novel rare variants in patients with cardiomyopathy, but assigning pathogenicity to these novel variants remains challenging.

Autophagy in Myocardial Differentiation and Cardiac Development

Autophagy represents an important biological process that contributes to cellular homeostasis. It is induced when the cell experiences stress, including nutrient and energy deprivation. For instance, the absence of nutrients and growth factors induces autophagy within minutes.1 Autophagy functions to protect cells against potential damage in association with exposure to stress, and thereby helps to defend cells and, subsequently, organs against dysfunction. There are multiple lines of evidence that autophagy has disease-preventing effects and, if disease still occurs, autophagy may limit disease severity.2 In addition, autophagy appears to play a key role in delaying the aging process.3,4 Article, see p e29 How does autophagy mediate such disease-preventing and disease-limiting effects? For damage control, cells generate double-membrane vesicles, called autophagosomes, which sequester portions of the cytosol, including proteins and organelles. After fusion of an autophagosome with a lysosome, the sequestered cytosolic contents are degraded. This process allows cells to eliminate and recycle …

Genetics of Cardiomyopathies in Children

Cardiomyopathies are diseases of the heart muscle leading to heart failure and/or an increased risk of arrhythmogenic sudden cardiac death. These disorders represent a major cause of morbidity and mortality in children. In childhood forms of cardiomyopathy, genetic etiologies are frequent, but non-genetic or acquired causes, such viral infection, also play a significant role. In the last twenty years, the genetic causes of cardiomyopathies have been increasingly identified and clinical correlations are beginning to be defined. Here we present an overview of the recent advances in our understanding of the genetics of cardiomyopathies in children and what is known about the pathophysiological mechanisms underlying these gene-related forms of disease.

Genetic causes of cardiomyopathy in children

Knowledge about the molecular basis of several diseases is steadily increasing; however our knowledge regarding the molecular basis of cardiomyopathies is still limited. Although the etiology of many inherited metabolic diseases accompanied by cardiomyopathy has been identified in the past decade, many of these entities are extremely rare, so that genetic studies are difficult to perform. Despite this, in some entities, the molecular and genetic basis of cardiomyopathy was identified. However, understanding of the molecular basis of cardiomyopathy is still in the beginning stages.