Inherited Cardiomyopathies and the Role of Mutations in Non-coding Regions of the Genome.
Ontology highlight
ABSTRACT:
SUBMITTER: Salman OF
PROVIDER: S-EPMC6028572 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Inherited Cardiomyopathies and the Role of Mutations in Non-coding Regions of the Genome.
Salman Oday F OF El-Rayess Hebah M HM Abi Khalil Charbel C Nemer Georges G Refaat Marwan M MM
Frontiers in cardiovascular medicine 20180626
Cardiomyopathies (CMs) are a group of cardiac pathologies caused by an intrinsic defect within the myocardium. The relative contribution of genetic mutations in the pathogenesis of certain CMs, such as hypertrophic cardiomyopathy (HCM), arrythmogenic right/left ventricular cardiomyopathy (ARVC) and left ventricular non-compacted cardiomyopathy (LVNC) has been established in comparison to dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM). The aim of this article is to review mutat ...[more]
Similar Datasets
Project description:BackgroundCardiomyopathies are a leading cause of progressive heart failure and sudden cardiac death; however, their genetic aetiology remains poorly understood. We hypothesised that variants in noncoding regulatory regions and oligogenic inheritance mechanisms may help close the diagnostic gap.MethodsWe first analysed whole-genome sequencing data of 143 parent-offspring trios from Genomics England 100,000 Genomes Project. We used gene panel testing and a phenotype-based, variant prioritisation framework called Exomiser to identify candidate genes in trios. To assess the contribution of noncoding DNVs to cardiomyopathies, we intersected DNVs with open chromatin sequences from single-cell ATAC-seq data of cardiomyocytes. We also performed a case-control analysis in an exome-negative cohort, including 843 probands and 19,467 controls, to assess the association between noncoding variants in known cardiomyopathy genes and disease.ResultsIn the trio analysis, a definite or probable genetic diagnosis was identified in 21 probands according to the American College of Medical Genetics guidelines. We identified novel DNVs in diagnostic-grade genes (RYR2, TNNT2, PTPN11, MYH7, LZR1, NKX2-5), and five cases harbouring a combination of prioritised variants, suggesting that oligogenic inheritance and genetic modifiers contribute to cardiomyopathies. Phenotype-based ranking of candidate genes identified in noncoding DNV analysis revealed JPH2 as the top candidate. Moreover, a case-control analysis revealed an enrichment of rare noncoding variants in regulatory elements of cardiomyopathy genes (p = .035, OR = 1.43, 95% Cl = 1.095-1.767) versus controls. Of the 25 variants associated with disease (p< 0.5), 23 are novel and nine are predicted to disrupt transcription factor binding motifs.ConclusionOur results highlight complex genetic mechanisms in cardiomyopathies and reveal novel genes for future investigations.
| S-EPMC9647983 | biostudies-literature
Project description:Point mutations are the most common cause of inherited diseases. Bioinformatics tools can help to predict the pathogenicity of mutations found during genetic screening, but they may work less well in determining the effect of point mutations in non-coding regions. In silico analysis of intronic variants can reveal their impact on the splicing process, but the consequence of a given substitution is generally not predictable. The aim of this study was to functionally test five intronic variants (MYBPC3-c.506-2A>C, MYBPC3-c.906-7G>T, MYBPC3-c.2308+3G>C, SCN5A-c.393-5C>A, and ACTC1-c.617-7T>C) found in five patients affected by inherited cardiomyopathies in the attempt to verify their pathogenic role. Analysis of the MYBPC3-c.506-2A>C mutation in mRNA from the peripheral blood of one of the patients affected by hypertrophic cardiac myopathy revealed the loss of the canonical splice site and the use of an alternative splicing site, which caused the loss of the first seven nucleotides of exon 5 (MYBPC3-G169AfsX14). In the other four patients, we generated minigene constructs and transfected them in HEK-293 cells. This minigene approach showed that MYBPC3-c.2308+3G>C and SCN5A-c.393-5C>A altered pre-mRNA processing, thus resulting in the skipping of one exon. No alterations were found in either MYBPC3-c.906-7G>T or ACTC1-c.617-7T>C. In conclusion, functional in vitro analysis of the effects of potential splicing mutations can confirm or otherwise the putative pathogenicity of non-coding mutations, and thus help to guide the patient's clinical management and improve genetic counseling in affected families.
| S-EPMC5133883 | biostudies-literature
Project description:The inherited cardiomyopathies, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC), have been frequently associated with mutations in sarcomeric proteins. In recent years, advances in DNA sequencing technology has allowed the study of the giant proteins of the sarcomere, such as titin and nebulin. Obscurin has been somewhat neglected in these studies, largely because its functional role is far from clear, although there was an isolated report in 2007 of obscurin mutations associated with HCM. Recently, whole exome sequencing methodology (WES) has been used to address mutations in OBSCN, the gene for obscurin, and OBSCN variants were found to be relatively common in inherited cardiomyopathies. In different studies, 5 OBSCN unique variants have been found in a group of 30 end-stage failing hearts, 6 OBSCN unique variants in 74 HCM cases and 3 OBSCN unique variants in 10 LVNC patients. As yet, the number of known potentially disease-causing OBSCN variants is quite small. The reason for this is that mutations in the OBSCN gene have not been recognised as potentially disease-causing until recently, and were not included in large-scale genetic surveys. OBSCN mutations may be causative of HCM, DCM and LVNC and other cardiomyopathies, or they may work in concert with other variants in the same or other genes to initiate the pathology. Currently, the function of obscurin is not well understood, but we anticipate that many more OBSCN variants linked to cardiomyopathy will be found when the large cohorts of patient sequences available are tested. It is to be hoped that the establishment of the importance of obscurin in pathology will stimulate a thorough investigation of obscurin function.
| S-EPMC5498328 | biostudies-other
Project description:Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of ?-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X). Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.
| S-EPMC3315208 | biostudies-literature
Project description:Latest advancements in genomics involving individuals from different races and geographical locations has led to the identification of thousands of common as well as rare genetic variants and copy number variations (CNVs). These studies have surprisingly revealed that the majority of genetic variation is not present within the coding region but rather in the non-coding region of the genome, which is also termed as "Medical Genome". This short review describes how mutations/variations within; regulatory sequences, architectural proteins and transcriptional regulators give rise to the aberrant gene expression profiles that drives cellular transformations and malignancies.
| S-EPMC7611228 | biostudies-literature
Project description:Cardiomyopathies due to genetic mutations are a heterogeneous group of disorders that comprise diseases of contractility, myocardial relaxation, and arrhythmias. Our goal here is to discuss a limited list of genetically inherited cardiomyopathies and the specific therapeutic strategies used to treat them.Research into the molecular pathophysiology of the development of these cardiomyopathies is leading to the development of novel treatment approaches. Therapies targeting these specific mutations with gene therapy vectors are on the horizon, while other therapies which indirectly affect the physiologic derangements of the mutations are currently being studied and used clinically. Many of these therapies are older medications being given new roles such as mexiletine for Brugada syndrome and diflunisal for transthyretin amyloid cardiomyopathy. A newer targeted therapy, the inhibitor of myosin ATPase MYK-461, has been shown to suppress the development of ventricular hypertrophy, fibrosis, and myocyte disarray and is being studied as a potential therapy in patients with hypertrophic cardiomyopathy. While this field is too large to be completely contained in a single review, we present a large cross section of recent developments in the field of therapeutics for inherited cardiomyopathies. New therapies are on the horizon, and their development will likely result in improved outcomes for patients inflicted by these conditions.
| S-EPMC5557031 | biostudies-literature
Project description:The normal function of the heart relies on a series of complex metabolic processes orchestrating the proper generation and use of energy. In this context, mitochondria serve a crucial role as a platform for energy transduction by supplying ATP to the varying demand of cardiomyocytes, involving an intricate network of pathways regulating the metabolic flux of substrates. The failure of these processes results in structural and functional deficiencies of the cardiac muscle, including inherited cardiomyopathies. These genetic diseases are characterized by cardiac structural and functional anomalies in the absence of abnormal conditions that can explain the observed myocardial abnormality, and are frequently associated with heart failure. Since their original description, major advances have been achieved in the genetic and phenotype knowledge, highlighting the involvement of metabolic abnormalities in their pathogenesis. This review provides a brief overview of the role of mitochondria in the energy metabolism in the heart and focuses on metabolic abnormalities, mitochondrial dysfunction, and storage diseases associated with inherited cardiomyopathies.
| S-EPMC6947282 | biostudies-literature
Project description:In sub-Saharan Africa (SSA), the burden of noncommunicable diseases (NCDs) is rising disproportionately in comparison to the rest of the world, affecting urban, semi-urban and rural dwellers alike. NCDs are predicted to surpass infections like human immunodeficiency virus, tuberculosis and malaria as the leading cause of mortality in SSA over the next decade. Heart failure (HF) is the dominant form of cardiovascular disease (CVD), and a leading cause of NCD in SSA. The main causes of HF in SSA are hypertension, cardiomyopathies, rheumatic heart disease, pericardial disease, and to a lesser extent, coronary heart disease. Of these, the cardiomyopathies deserve greater attention because of the relatively poor understanding of mechanisms of disease, poor outcomes and the disproportionate impact they have on young, economically active individuals. Morphofunctionally, cardiomyopathies are classified as dilated, hypertrophic, restrictive and arrhythmogenic; regardless of classification, at least half of these are inherited forms of CVD. In this review, we summarise all studies that have investigated the incidence of cardiomyopathy across Africa, with a focus on the inherited cardiomyopathies. We also review data on the molecular genetic underpinnings of cardiomyopathy in Africa, where there is a striking lack of studies reporting on the genetics of cardiomyopathy. We highlight the impact that genetic testing, through candidate gene screening, association studies and next generation sequencing technologies such as whole exome sequencing and targeted resequencing has had on the understanding of cardiomyopathy in Africa. Finally, we emphasise the need for future studies to fill large gaps in our knowledge in relation to the genetics of inherited cardiomyopathies in Africa.
| S-EPMC7225421 | biostudies-literature
Project description:IntroductionBasal cardiovascular risk assessment in cardio-oncology is essential. Integrating clinical information, ECG and transthoracic echocardiogram can identify concealed inherited cardiomyopathies (ICMPs) with potential added risk of cardiotoxicity. We aimed to evaluate the impact of our Cardio-Oncology Unit design in detecting concealed ICMPs.MethodsWe carried out a retrospective study of all consecutive breast cancer patients referred to the Cardio-Oncology Unit for cardiac evaluation (2020-2022). ICMPs diagnosis was provided according to ESC guidelines and underwent genetic testing. ICMPs prevalence in this cohort was compared to the highest and lowest frequency reported in the general population.ResultsAmong 591 breast cancer patients, we identified eight patients with ICMPs: one arrhythmogenic cardiomyopathy (ACM), three familial non-ischemic dilated cardiomyopathy (DCM), three hypertrophic cardiomyopathy (HCM) and one left ventricular non-compaction cardiomyopathy (LVNC), which has now been reclassified as non-dilated left ventricular cardiomyopathy. The number of ICMPs identified was within the expected range (neither overdiagnosed nor overlooked): ACM 0.0017 vs. 0.0002-0.001 (p 0.01-0.593); DCM 0.0051 vs. 0.002-0.0051 (p 0.094-0.676); HCM 0.005 vs. 0.0002-0.002 (p < 0.001-0.099); LVCN 0.0017 vs. 0.00014-0.013 (p 0.011-0.015). Genetic testing identified a pathogenic FLNC variant and two pathogenic TTN variants.ConclusionOpportunistic screening of ICMPs during basal cardiovascular risk assessment can identify high-risk cancer patients who benefit from personalized medicine and enables extension of prevention strategies to all available relatives at concealed high cardiovascular risk.
| S-EPMC10780282 | biostudies-literature
Project description:Multiple sclerosis (MS) is the most common neurological disorder in young adults. Despite extensive studies, only a fraction of MS heritability has been explained, with association studies focusing primarily on protein-coding genes, essentially for the difficulty of interpreting non-coding features. However, non-coding RNAs (ncRNAs) and functional elements, such as super-enhancers (SE), are crucial regulators of many pathways and cellular mechanisms, and they have been implicated in a growing number of diseases. In this work, we searched for possible enrichments in non-coding elements at MS genome-wide associated loci, with the aim to highlight their possible involvement in the susceptibility to the disease. We first reconstructed the linkage disequilibrium (LD) structure of the Italian population using data of 727,478 single-nucleotide polymorphisms (SNPs) from 1,668 healthy individuals. The genomic coordinates of the obtained LD blocks were intersected with those of the top hits identified in previously published MS genome-wide association studies (GWAS). By a bootstrapping approach, we hence demonstrated a striking enrichment of non-coding elements, especially of circular RNAs (circRNAs) mapping in the 73 LD blocks harboring MS-associated SNPs. In particular, we found a total of 482 circRNAs (annotated in publicly available databases) vs. a mean of 194 ± 65 in the random sets of LD blocks, using 1,000 iterations. As a proof of concept of a possible functional relevance of this observation, we experimentally verified that the expression levels of a circRNA derived from an MS-associated locus, i.e., hsa_circ_0043813 from the STAT3 gene, can be modulated by the three genotypes at the disease-associated SNP. Finally, by evaluating RNA-seq data of two cell lines, SH-SY5Y and Jurkat cells, representing tissues relevant for MS, we identified 18 (two novel) circRNAs derived from MS-associated genes. In conclusion, this work showed for the first time that MS-GWAS top hits map in LD blocks enriched in circRNAs, suggesting circRNAs as possible novel contributors to the disease pathogenesis.
| S-EPMC6304422 | biostudies-literature