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European Journal of Medical Genetics Sep 2021Over 70 genes that encode different cell components have been involved in the aetiology of dilated cardiomyopathy. Genotype-phenotype interactions are an unsolved...
BACKGROUND
Over 70 genes that encode different cell components have been involved in the aetiology of dilated cardiomyopathy. Genotype-phenotype interactions are an unsolved problem, and to a large extent the effects of mutations in the expression mechanisms involved in the disease remain unknown, although associations are increasingly being established which have clinical and prognostic implications.
METHODS AND RESULTS
The objective of our work was to describe our population that has cardiomyopathy associated with mutations in the gene RBM20, and study the genotype-phenotype relationship. We studied 8 cases undergoing follow-up at our Unit, and collected data for demographic, clinical and diagnostic testing variables. The mean age on diagnosis was 55 years [52-59], with a median follow-up of 31.5 months [26.0-67.3]. It is worth noting that 62.5% of the patients in our group had a history of cardiomyopathy in first degree relatives, and 37.5% of them had a family history of sudden death. One of the genetic variations of the sample was shared by three subjects who had no apparent family relationship with each other, and this variation had not been described in controls. It is also interesting that arrhythmic events were found in 37.5% of the sample, and 50% of patients had an indication for implantable cardiac defibrillator.
CONCLUSION
This is the first analysis of patients with RBM20 mutations conducted in our country, and it indicates a profile with prominent arrhythmogenesis, a high penetrance of familial cardiomyopathy, and sudden death.
Topics: Cardiomyopathy, Dilated; Disease Progression; Female; Humans; Male; Middle Aged; Mutation, Missense; Pedigree; Phenotype; RNA-Binding Proteins
PubMed: 34174465
DOI: 10.1016/j.ejmg.2021.104278 -
Minerva Cardiology and Angiology Apr 2022Non-ischemic dilated cardiomyopathy (NI-DCM) represents a specific etiology of systolic heart failure that usually affect young individuals with a genetic background in... (Review)
Review
Non-ischemic dilated cardiomyopathy (NI-DCM) represents a specific etiology of systolic heart failure that usually affect young individuals with a genetic background in up to 40% of cases. Behind the term NI-DCM there is a spectrum of different diseases, and an accurate etiological classification appears pivotal for the clinical management and prognostic stratification of these patients. In the last years the prognosis of NI-DCM patients dramatically improved thanks to the progresses in medical treatment/ device therapy and earlier diagnosis especially in familial context. In this review we summarize the actual state of art in the management of these patients. In the era of precision medicine, a lot of progresses have been made to expand our knowledge on the management of NI-DCM patients. A complex interaction between genotype and external triggers is the main determinant of the clinical phenotype in NI-DCM, and a lot of efforts must be done by clinicians to systematically rule out all the possible causes involved in the pathogenesis. Progresses in cardiac imaging and familial screening led us to detect subtle abnormalities in the initial phase of the disease and also helped us to furtherly stratify the prognosis and arrhythmic risk of these patients. It is plausible that a more precise etiological classification will be needed in the near future. NI-DCM contains a spectrum of different diseases. Proper etiological classification, early diagnosis and strict follow-up are essential to tailor care of these patients.
Topics: Cardiomyopathy, Dilated; Early Diagnosis; Forecasting; Humans; Myocardial Ischemia; Prognosis
PubMed: 34338487
DOI: 10.23736/S2724-5683.21.05736-7 -
Trends in Cardiovascular Medicine Nov 2023Lyme carditis is a well-established manifestation of early disseminated Lyme infection, yet the relationship between late disseminated Lyme disease and the development... (Review)
Review
Lyme carditis is a well-established manifestation of early disseminated Lyme infection, yet the relationship between late disseminated Lyme disease and the development of dilated cardiomyopathy (DCM) remains unclear. The present systematic review aims to summarize existing literature on the association between late disseminated Lyme disease and DCM. A systematic review was conducted in PubMed, Embase, CENTRAL, and MEDLINE databases, after which a total of 11 observational studies (n = 771) were ultimately included for final data extraction. Although most studies (7/11) identified evidence associating Borrelia-infection with DCM, further research is required to isolate late disseminated Borrelia infection as a causative agent of DCM.
Topics: Humans; Cardiomyopathy, Dilated; Lyme Disease
PubMed: 35667636
DOI: 10.1016/j.tcm.2022.05.010 -
Journal of Cardiovascular Translational... Dec 2023Cardiomyopathy has variable penetrance. We analyzed age and sex-related genetic differences in 1,397 cardiomyopathy patients (Ontario, UK) with whole genome sequencing....
Cardiomyopathy has variable penetrance. We analyzed age and sex-related genetic differences in 1,397 cardiomyopathy patients (Ontario, UK) with whole genome sequencing. Pediatric cases (n = 471) harbored more deleterious protein-coding variants in Tier 1 cardiomyopathy genes compared to adults (n = 926) (34.6% vs 25.9% respectively, p = 0.0015), with variant enrichment in constrained coding regions. Pediatric patients had a higher burden of sarcomere and lower burden of channelopathy gene variants compared to adults. Specifically, pediatric patients had more MYH7 and MYL3 variants in hypertrophic cardiomyopathy, and fewer TTN truncating variants in dilated cardiomyopathy. MYH7 variants clustered in the myosin head and neck domains in children. OBSCN was a top mutated gene in adults, enriched for protein-truncating variants. In dilated cardiomyopathy, female patients had a higher burden of z-disc gene variants compared to males. Genetic differences may explain age and sex-related variability in cardiomyopathy penetrance. Genotype-guided predictions of age of onset can inform pre-test genetic counseling. Pediatric cardiomyopathy patients were more likely to be genotype-positive than adults with a higher burden of variants in MYH7, MYL3, TNNT2, VCL. Adults had a higher burden of OBSCN and TTN variants. Females with dilated cardiomyopathy (DCM) had a higher burden of z-disc gene variants compared to males.
Topics: Adult; Humans; Male; Female; Child; Cardiomyopathy, Dilated; Mutation; Sex Characteristics; Cardiomyopathies; Genotype; Cardiomyopathy, Hypertrophic
PubMed: 37477868
DOI: 10.1007/s12265-023-10411-8 -
BMC Cardiovascular Disorders Jul 2022The pathogenic mechanism of dilated cardiomyopathy (DCM) remains to be defined. This study aimed to identify hub genes and immune cells that could serve as potential...
BACKGROUND
The pathogenic mechanism of dilated cardiomyopathy (DCM) remains to be defined. This study aimed to identify hub genes and immune cells that could serve as potential therapeutic targets for DCM.
METHODS
We downloaded four datasets from the Gene Expression Omnibus (GEO) database: GSE141910, GSE3585, GSE42955 and GSE79962. Weighted gene coexpression network analysis (WGCNA) and differential expression analysis were performed to identify gene panels related to DCM. Meanwhile, the CIBERSORT algorithm was used to estimate the immune cells in DCM tissues. Multiple machine learning approaches were used to screen the hub genes and immune cells. Finally, the diagnostic value of the hub genes was assessed by receiver operating characteristic (ROC) analysis. An experimental mouse model of dilated cardiomyopathy was used to validate the bioinformatics results.
RESULTS
FRZB and EXT1 were identified as hub biomarkers, and the ROC curves suggested an excellent diagnostic ability of the above genes for DCM. In addition, naive B cells were upregulated in DCM tissues, while eosinophils, M2 macrophages, and memory CD4 T cells were downregulated in DCM tissues. The increase in two hub genes and naive B cells was validated in animal experiments.
CONCLUSION
These results indicated that FRZB and EXT1 could be used as promising biomarkers, and eosinophils, M2 macrophages, resting memory CD4 T cells and naive B cells may also affect the occurrence of DCM.
Topics: Animals; Biomarkers; Cardiomyopathy, Dilated; Gene Expression Profiling; Gene Regulatory Networks; Mice; RNA-Seq
PubMed: 35850644
DOI: 10.1186/s12872-022-02759-7 -
Journal of the American Heart... Jun 2020
Topics: Cardiomyopathy, Dilated; Child; Genetic Testing; Humans; Pedigree; Retrospective Studies
PubMed: 32458723
DOI: 10.1161/JAHA.120.016910 -
European Journal of Heart Failure Jan 2024
Topics: Humans; Cardiomyopathy, Dilated; Coronary Artery Disease; Heart Failure; Coronary Angiography; Echocardiography
PubMed: 37994286
DOI: 10.1002/ejhf.3095 -
Circulation. Genomic and Precision... Oct 2023Many cardiovascular disorders propel the development of advanced heart failure that necessitates cardiac transplantation. When treatable causes are excluded, studies to...
BACKGROUND
Many cardiovascular disorders propel the development of advanced heart failure that necessitates cardiac transplantation. When treatable causes are excluded, studies to define causes are often abandoned, resulting in a diagnosis of end-stage idiopathic cardiomyopathy. We studied whether DNA sequence analyses could identify unrecognized causes of end-stage nonischemic cardiomyopathy requiring heart transplantation and whether the prevalence of genetic causes differed from ambulatory cardiomyopathy cases.
METHODS
We performed whole exome and genome sequencing of 122 explanted hearts from 101 adult and 21 pediatric patients with idiopathic cardiomyopathy from a single center. Data were analyzed for pathogenic/likely pathogenic variants in nuclear and mitochondrial genomes and assessed for nonhuman microbial sequences. The frequency of damaging genetic variants was compared among cardiomyopathy cohorts with different clinical severity.
RESULTS
Fifty-four samples (44.3%) had pathogenic/likely pathogenic cardiomyopathy gene variants. The frequency of pathogenic variants was similar in pediatric (42.9%) and adult (43.6%) samples, but the distribution of mutated genes differed (=8.30×10). The prevalence of causal genetic variants was significantly higher in end-stage than in previously reported ambulatory adult dilated cardiomyopathy cases (<0.001). Among remaining samples with unexplained causes, no damaging mitochondrial variants were identified, but 28 samples contained parvovirus genome sequences, including 2 samples with 6- to 9-fold higher levels than the overall mean levels in other samples.
CONCLUSIONS
Pathogenic variants and viral myocarditis were identified in 45.9% of patients with unexplained end-stage cardiomyopathy. Damaging gene variants are significantly more frequent among transplant compared with patients with ambulatory cardiomyopathy. Genetic analyses can help define cause of end-stage cardiomyopathy to guide management and risk stratification of patients and family members.
Topics: Adult; Humans; Child; Cardiomyopathies; Cardiomyopathy, Dilated; Heart Transplantation; Heart Failure
PubMed: 37767697
DOI: 10.1161/CIRCGEN.123.004062 -
International Journal of Cardiology Mar 2024
Topics: Humans; Cardiomyopathy, Dilated; Prognosis; Ventricular Function, Left
PubMed: 38101701
DOI: 10.1016/j.ijcard.2023.131655 -
Journal of Translational Medicine Jul 2023Dilated cardiomyopathy (DCM) is one of the most frequent causes of heart failure and heart transplantation (HTx). The genetic basis of DCM among patients undergoing HTx...
BACKGROUND
Dilated cardiomyopathy (DCM) is one of the most frequent causes of heart failure and heart transplantation (HTx). The genetic basis of DCM among patients undergoing HTx remains to be further studied. This study aimed to characterize the genetic basis of DCM HTx in the Chinese population.
METHODS
In total, 208 unrelated DCM patients who underwent HTx at Fuwai Hospital between June 2004 and June 2017 were included in this study. Whole-exome sequencing (WES) was performed for all patients. Gene burden analysis, variant classification, and genotype-phenotype correlation analysis were subsequently performed.
RESULTS
After completing the bioinformatics analysis, gene burden analysis suggested that titin (TTN), filamin C (FLNC) and lamin A/C (LMNA) were significantly enriched with rare protein-altering variants. The frequencies of TTN and FLNC truncating variants in our cohort were 18.8% and 8.7%, respectively. Among the 165 rare variants in high evidence DCM-related genes, 27 (16.4%) and 59 (35.8%) were interpreted as pathogenic (P) and likely pathogenic (LP), respectively. In addition, 41 (47.7%) and 16 (18.6%) of these 86 P/LP variants are located in TTN and FLNC, respectively. The FLNC group contained more patients with NYHA class IV than the P/LP-negative group (FLNC, 16/18 vs. P/LP-negative, 81/123, P = 0.049).
CONCLUSIONS
Based on WES, we provided a primary genetic spectrum of DCM patients undergoing HTx in the Chinese population. TTN and FLNC harbour the most P/LP variants. FLNC truncation may lead to severe clinical symptoms in DCM patients.
Topics: Humans; Cardiomyopathy, Dilated; East Asian People; Exome Sequencing; Genetic Association Studies; Heart Transplantation; Mutation
PubMed: 37461109
DOI: 10.1186/s12967-023-04282-5