scholarly journals Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features

2021 ◽  
Author(s):  
Alice Ghidoni ◽  
Perry M. Elliott ◽  
Petros Syrris ◽  
Hugh Calkins ◽  
Cynthia A. James ◽  
...  
Keyword(s):  
Heart Failure ◽  
Clinical Features ◽  
Genetic Screening ◽  
Rare Variants ◽  
Family Members ◽  
Arrhythmogenic Cardiomyopathy ◽  
Cascade Screening ◽  
Pathogenic Variants ◽  
Fatty Replacement ◽  
The Right

Background - Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibro-fatty replacement of the right and/or left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants, in the non-desmosomal cadherin 2 ( CDH2 ), a novel genetic substrate of ACM. Methods - A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2 -positive probands, and clinical evaluation was assessed. Results - Genetic screening of CDH2 led to the identification of 7 rare variants: five, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2 -positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and/or sudden cardiac death occurred in 5/9 (56%). Conclusions - In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2 -ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.

scholarly journals Yield of peripheral sodium channels gene screening in pure small fibre neuropathy

2018 ◽  
Vol 90 (3) ◽  
pp. 342-352 ◽  
Author(s):  
Ivo Eijkenboom ◽  
Maurice Sopacua ◽  
Janneke G J Hoeijmakers ◽  
Bianca T A de Greef ◽  
Patrick Lindsey ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Clinical Features ◽  
Genetic Screening ◽  
Clinical Genetic ◽  
Genetic Studies ◽  
Small Fibre Neuropathy ◽  
Reference Centre ◽  
Pathogenic Variants ◽  
Small Fibre ◽  
Genetic Science

BackgroundNeuropathic pain is common in peripheral neuropathy. Recent genetic studies have linked pathogenic voltage-gated sodium channel (VGSC) variants to human pain disorders. Our aims are to determine the frequency of SCN9A, SCN10A and SCN11A variants in patients with pure small fibre neuropathy (SFN), analyse their clinical features and provide a rationale for genetic screening.MethodsBetween September 2009 and January 2017, 1139 patients diagnosed with pure SFN at our reference centre were screened for SCN9A, SCN10A and SCN11A variants. Pathogenicity of variants was classified according to established guidelines of the Association for Clinical Genetic Science and frequencies were determined. Patients with SFN were grouped according to the VGSC variants detected, and clinical features were compared.ResultsAmong 1139 patients with SFN, 132 (11.6%) patients harboured 73 different (potentially) pathogenic VGSC variants, of which 50 were novel and 22 were found in ≥ 1 patient. The frequency of (potentially) pathogenic variants was 5.1% (n=58/1139) for SCN9A, 3.7% (n=42/1139) for SCN10A and 2.9% (n=33/1139) for SCN11A. Only erythromelalgia-like symptoms and warmth-induced pain were significantly more common in patients harbouring VGSC variants.Conclusion(Potentially) pathogenic VGSC variants are present in 11.6% of patients with pure SFN. Therefore, genetic screening of SCN9A, SCN10A and SCN11A should be considered in patients with pure SFN, independently of clinical features or underlying conditions.

scholarly journals Arrhythmogenic Cardiomyopathy

2019 ◽  
Vol 87 (11-12) ◽  
pp. 599-618
Author(s):  
Blaž Podgoršek ◽  
Gregor Poglajen ◽  
Andraž Cerar ◽  
Matjaž Šinkovec ◽  
Bojan Vrtovec
Keyword(s):  
Task Force ◽  
Current Knowledge ◽  
Diagnostic Yield ◽  
Treatment Strategies ◽  
Arrhythmogenic Cardiomyopathy ◽  
Icd Implantation ◽  
Fatty Replacement ◽  
Current Task ◽  
Advanced Stages ◽  
The Right

Arrhythmogenic cardiomyopathy (AC) is a genetic disease of the myocardium characterized by fibro-fatty replacement of the apoptotic myocardium. It primarily affects the right ventricle, however in advanced stages of the disease the left ventricle can also be significantly affected. AC is a challenging diagnosis, especially in the early stages of the disease, and should be considered in all patients presenting with palpitations, syncope or sudden cardiac death when other, more common causes of these symptoms/signs are excluded. In patients with suspected AC, evaluation according to the current Task Force Criteria should be applied to achieve optimal diagnostic yield. The main therapeutic concern in AC patients is the prevention of SCD, and thus all patients with established diagnosis have to be evaluated for potential ICD implantation, which is indicated in the majority of symptomatic patients. In this narrative review we aim to outline current knowledge on the pathophysiology, diagnosis and treatment strategies of AC.

scholarly journals The Role of MicroRNAs in Arrhythmogenic Cardiomyopathy: Biomarkers or Innocent Bystanders of Disease Progression?

2020 ◽  
Vol 21 (17) ◽  
pp. 6434
Author(s):  
Maria Bueno Marinas ◽  
Rudy Celeghin ◽  
Marco Cason ◽  
Gaetano Thiene ◽  
Cristina Basso ◽  
...  
Keyword(s):  
Gene Expression Regulation ◽  
Phenotypic Variability ◽  
Incomplete Penetrance ◽  
Primary Role ◽  
Arrhythmogenic Cardiomyopathy ◽  
Small Noncoding Rnas ◽  
Early Disease Detection ◽  
Pathogenic Variants ◽  
Fatty Replacement ◽  
Genes Encoding

Arrhythmogenic cardiomyopathy (AC) is an inherited cardiac disease characterized by a progressive fibro-fatty replacement of the working myocardium and by life-threatening arrhythmias and risk of sudden cardiac death. Pathogenic variants are identified in nearly 50% of affected patients mostly in genes encoding for desmosomal proteins. AC incomplete penetrance and phenotypic variability advocate that other factors than genetics may modulate the disease, such as microRNAs (miRNAs). MiRNAs are small noncoding RNAs with a primary role in gene expression regulation and network of cellular processes. The implication of miRNAs in AC pathogenesis and their role as biomarkers for early disease detection or differential diagnosis has been the objective of multiple studies employing diverse designs and methodologies to detect miRNAs and measure their expression levels. Here we summarize experiments, evidence, and flaws of the different studies and hitherto knowledge of the implication of miRNAs in AC pathogenesis and diagnosis.

scholarly journals Machine learning modelling of blood lipid biomarkers in familial hypercholesterolaemia versus polygenic/environmental dyslipidaemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marta Correia ◽  
Eva Kagenaar ◽  
Daniël Bernardus van Schalkwijk ◽  
Mafalda Bourbon ◽  
Margarida Gama-Carvalho
Keyword(s):  
Machine Learning ◽  
Genetic Screening ◽  
Familial Hypercholesterolaemia ◽  
Blood Lipid ◽  
Disease Genes ◽  
Cascade Screening ◽  
Clinical Criteria ◽  
Screening Programs ◽  
Pathogenic Variants ◽  
Premature Cardiovascular Disease

AbstractFamilial hypercholesterolaemia increases circulating LDL-C levels and leads to premature cardiovascular disease when undiagnosed or untreated. Current guidelines support genetic testing in patients complying with clinical diagnostic criteria and cascade screening of their family members. However, most of hyperlipidaemic subjects do not present pathogenic variants in the known disease genes, and most likely suffer from polygenic hypercholesterolaemia, which translates into a relatively low yield of genetic screening programs. This study aims to identify new biomarkers and develop new approaches to improve the identification of individuals carrying monogenic causative variants. Using a machine-learning approach in a paediatric dataset of individuals, tested for disease causative genes and with an extended lipid profile, we developed new models able to classify familial hypercholesterolaemia patients with a much higher specificity than currently used methods. The best performing models incorporated parameters absent from the most common FH clinical criteria, namely apoB/apoA-I, TG/apoB and LDL1. These parameters were found to contribute to an improved identification of monogenic individuals. Furthermore, models using only TC and LDL-C levels presented a higher specificity of classification when compared to simple cut-offs. Our results can be applied towards the improvement of the yield of genetic screening programs and corresponding costs.

scholarly journals Prevalence and Clinical Features of Autosomal Dominant and Recessive TMC1-Associated Hearing Loss.

2021 ◽  
Author(s):  
Shin-ya Nishio ◽  
Shin-ichi Usami
Keyword(s):  
Hearing Loss ◽  
Clinical Features ◽  
Autosomal Recessive ◽  
Haplotype Analysis ◽  
Autosomal Dominant ◽  
Founder Mutation ◽  
Family Members ◽  
Causative Gene ◽  
Pathogenic Variants ◽  
Syndromic Hearing Loss

Abstract TMC1 is a causative gene for both autosomal dominant non-syndromic hearing loss (DFNA36) and autosomal recessive non-syndromic hearing loss (DFNB7/11). To date, 125 pathogenic variants in TMC1 have been reported. Most of the TMC1 variants are responsible for autosomal recessive hearing loss, with only 7 variants reported as causative for DFNA36. Here we reported the prevalence of TMC1-associated hearing loss in a large non-syndromic hearing loss cohort of about 12,000 subjects. As a result, we identified 26 probands with TMC1-associated hearing loss and the estimated prevalence of TMC1-associated hearing loss in the Japanese hearing loss cohort to be 0.18% among all patients. Among the 26 probands with TMC1-associated hearing loss, 15 cases were identified from autosomal dominant hearing loss families. By using the audiometric data from the probands, family members and previously reported cases, we evaluated the hearing deterioration speed for DFNA36 patients. In addition, we performed haplotype analysis for 11 unrelated autosomal dominant hearing loss families carrying the same variant TMC1: NM_138691:c.1627G > A:p.D543N. The results clearly indicated that the same haplotype was present despite of families being unrelated, supporting the contention that this variant occurred by founder mutation.

scholarly journals Update on Genes Associated with Arrhythmogenic Cardiomyopathy

2020 ◽  
Author(s):  
Marta Vallverdú-Prats ◽  
Mireia Alcalde ◽  
Georgia Sarquella-Brugada ◽  
Sergi Cesar ◽  
Elena Arbelo ◽  
...  
Keyword(s):  
Rare Variants ◽  
Correct Diagnosis ◽  
Phenotypic Expression ◽  
Genetic Alterations ◽  
Left Ventricular ◽  
Incomplete Penetrance ◽  
Arrhythmogenic Cardiomyopathy ◽  
Young Males ◽  
Genes Encoding ◽  
The Right

Arrhythmogenic cardiomyopathy is a rare genetic entity characterized by progressive fibro-fatty replacement of myocardium leading to malignant arrhythmias, syncope, and sudden cardiac death. Mostly it affects the right ventricle, but cases have also been described with biventricular and even isolated left ventricular involvement. The disease affects mainly young males and arrhythmias are usually induced by exercise. Arrhythmogenic cardiomyopathy has a genetic origin and is basically caused by deleterious alterations in genes encoding desmosomal proteins, especially plakophilin-2. To date, more than 400 rare genetic alterations have been identified in 18 genes, mainly with autosomal dominant inheritance, but some recessive forms have also been reported (Naxos disease and Carvajal syndrome). A comprehensive genetic analysis identifies a rare variant as potential cause of the disease in around 60% of patients, suggesting the existence of unknown genes as well as other genome alterations not yet discovered. Genetic interpretation classifies some of these rare variants as ambiguous, playing an uncertain role in arrhythmogenic cardiomyopathy. This makes a proper translation of genetic data into clinical practice difficult. Moreover, incomplete penetrance and variable phenotypic expression makes it difficult to arrive at the correct diagnosis. In the present chapter, we focus on recent advances in the knowledge regarding the genetic basis of arrhythmogenic cardiomyopathy.

scholarly journals Prevalence and clinical features of autosomal dominant and recessive TMC1-associated hearing loss

2021 ◽  
Author(s):  
Shin-ya Nishio ◽  
Shin-ichi Usami
Keyword(s):  
Hearing Loss ◽  
Clinical Features ◽  
Autosomal Recessive ◽  
Haplotype Analysis ◽  
Autosomal Dominant ◽  
Founder Mutation ◽  
Family Members ◽  
Causative Gene ◽  
Pathogenic Variants ◽  
Syndromic Hearing Loss

AbstractTMC1 is a causative gene for both autosomal dominant non-syndromic hearing loss (DFNA36) and autosomal recessive non-syndromic hearing loss (DFNB7/11). To date, 125 pathogenic variants in TMC1 have been reported. Most of the TMC1 variants are responsible for autosomal recessive hearing loss, with only 8 variants reported as causative for DFNA36. Here, we reported the prevalence of TMC1-associated hearing loss in a large non-syndromic hearing loss cohort of about 12,000 subjects. As a result, we identified 26 probands with TMC1-associated hearing loss, with the estimated prevalence of TMC1-associated hearing loss in the Japanese hearing loss cohort being 0.17% among all patients. Among the 26 probands with TMC1-associated hearing loss, 15 cases were identified from autosomal dominant hearing loss families. Based on the audiometric data from the probands, family members and previously reported cases, we evaluated hearing deterioration for DFNA36 patients. In addition, we performed haplotype analysis for 11 unrelated autosomal dominant hearing loss families carrying the same variant TMC1: NM_138691:c.1627G > A:p.Asp543Asn. The results clearly indicated that the same haplotype was present despite the families being unrelated, supporting the contention that this variant occurred by founder mutation.

scholarly journals GJB1 Gene Analysis in Two Extended Families with X-Linked Charcot-Marie-Tooth Disease

2021 ◽  
pp. 422-428
Author(s):  
Sabine Kovale ◽  
Ruta Terauda ◽  
Elina Millere ◽  
Gita Taurina ◽  
Daiga Murmane ◽  
...  
Keyword(s):  
Family Members ◽  
Type I ◽  
Cascade Screening ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Extended Families ◽  
Pathogenic Variants ◽  
The Family ◽  
Neurological Phenotype ◽  
Tooth Disease

X-linked Charcot-Marie-Tooth (CMT) disease type I (CMTX1) is the second most frequent type of CMT disease caused by pathogenic variants in the <i>GJB1</i> gene. We described 2 extended cases (families) with CMTX1 with identified pathogenic variants – p.Val139Met and p.Arg215Trp. In both the families, neurological symptoms started earlier in male than in female patients. In some family members, molecular diagnostics was performed prior to neurological investigation due to family cascade screening. There was variable neurological phenotype representing CMT. Conclusions: There is a large clinical heterogeneity in CMTX, even amongst the family members.

scholarly journals Heart Failure in Patients with Arrhythmogenic Cardiomyopathy

2021 ◽  
Vol 10 (20) ◽  
pp. 4782
Author(s):  
Shi Chen ◽  
Liang Chen ◽  
Firat Duru ◽  
Shengshou Hu
Keyword(s):  
Heart Failure ◽  
Cardiac Death ◽  
Research Progress ◽  
Arrhythmogenic Cardiomyopathy ◽  
Young Athletes ◽  
Management Guidelines ◽  
Great Achievement ◽  
Inherited Cardiomyopathy ◽  
Fatty Replacement ◽  
Long Time

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited cardiomyopathy characterized as fibro-fatty replacement, and a common cause for sudden cardiac death in young athletes. Development of heart failure (HF) has been an under-recognized complication of ACM for a long time. The current clinical management guidelines for HF in ACM progression have nowadays been updated. Thus, a comprehensive review for this great achievement in our understanding of HF in ACM is necessary. In this review, we aim to describe the research progress on epidemiology, clinical characteristics, risk stratification and therapeutics of HF in ACM.

scholarly journals 430 Diagnosis and management of a case of biventricular arrhythmogenic cardiomyopathy: a case report

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Luigia Gionti ◽  
Livio Imparato ◽  
Aniello Viggiano ◽  
Maria Angela Losi ◽  
Giuseppe Gargiulo ◽  
...  
Keyword(s):  
Tissue Characterization ◽  
Young Patients ◽  
Arrhythmogenic Cardiomyopathy ◽  
Icd Implantation ◽  
Electrophysiologic Study ◽  
Premature Ventricular Contractions ◽  
Variant Of Uncertain Significance ◽  
Fatty Replacement ◽  
History Of ◽  
The Right

Abstract Arrhythmogenic cardiomyopathy (ACM) is a genetically determined heart muscle disorder characterized by fibro-fatty replacement of myocardium which may affect the right ventricle (‘dominant right’ variant), the left ventricle (‘dominant left’ variant) or both (‘biventricular disease’ variant). Despite of ACM is one of the main causes of sudden cardiac death (SCD) in young people and athletes as well, the diagnosis of this complex clinical entity still remains a challenge. We report on a case of a 29 years old non-athletic woman with family history of SCD and a long-standing personal history of palpitations leading to frequent accesses to the Accident & Emergency Department. Her echocardiogram was normal while twelve leads ECG revealed negative T waves in the right precordial leads (V1–V3) and post-excitation epsilon waves. ECG Holter monitoring recorded frequent (up to 17 000 in 24 h) polymorphic premature ventricular contractions (PVCs) seldom organized in couplets or triplets. She was followed-up in our clinic and started on Propanolol 40 mg bid with slight relief of symptoms and reduction of PVCs. Cardiac magnetic resonance (CMR) showed regional dyskinesia of both ventricles and RV dilatation. Moreover, tissue characterization findings revealed the presence of diffuse subepicardial late gadolinium enhancement (LGE) of the LV. Genetic analysis was performed and a variant of uncertain significance (VUS) in Desmoplakin was identified. Non sustained monomorphic ventricular tachycardia was induced during electrophysiologic study by programmed ventricular stimulation. In light of these results, we diagnosed biventricular ACM and, after carefully discussion with the patient, a subcutaneous implantable cardioverter defibrillator (ICD) was implanted. The present case should be a persisting reminder that must be considered more than just a single diagnostic tool when dealing with arrhythmic presentations especially in young patients and the importance of contrast CMR along with genetic testing in order to aid clinicians in the demanding selection of the best candidates for ICD implantation.

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