scholarly journals Clinical Implications of the Genetic Architecture of Dilated Cardiomyopathy

2020 ◽  
Vol 22 (12) ◽  
Author(s):  
Lisa D. Wilsbacher
Keyword(s):  
Genetic Testing ◽  
Dilated Cardiomyopathy ◽  
Ventricular Arrhythmias ◽  
Genetic Architecture ◽  
Genetic Diagnosis ◽  
Clinical Approach ◽  
Loss Of Function ◽  
Increase Risk ◽  
Life Threatening ◽  
New Evidence

Abstract Purpose of Review Dilated cardiomyopathy (DCM) frequently involves an underlying genetic etiology, but the clinical approach for genetic diagnosis and application of results in clinical practice can be complex. Recent Findings International sequence databases described the landscape of genetic variability across populations, which informed guidelines for the interpretation of DCM gene variants. New evidence indicates that loss-of-function mutations in filamin C (FLNC) contribute to DCM and portend high risk of ventricular arrhythmia. Summary A clinical framework aids in referring patients for DCM genetic testing and applying results to patient care. Results of genetic testing can change medical management, particularly in a subset of genes that increase risk for life-threatening ventricular arrhythmias, and can influence decisions for defibrillator therapy. Clinical screening and cascade genetic testing of family members should be diligently pursued to identify those at risk of developing DCM.

scholarly journals Considering complexity in the genetic evaluation of dilated cardiomyopathy

Heart ◽  
2020 ◽  
Vol 107 (2) ◽  
pp. 106-112
Author(s):  
Elizabeth Jordan ◽  
Ray E Hershberger
Keyword(s):  
At Risk ◽  
Genetic Testing ◽  
Dilated Cardiomyopathy ◽  
Genetic Architecture ◽  
Rare Variants ◽  
Genetic Evaluation ◽  
Clinical Genetics ◽  
Mendelian Disease ◽  
Clinical Genetic ◽  
Actionable Variants

Dilated cardiomyopathy (DCM) is a cardiovascular disease of genetic aetiology that causes substantial morbidity and mortality, and presents considerable opportunity for disease mitigation and prevention in those at risk. Foundational to the process of caring for patients diagnosed with DCM is a clinical genetic evaluation, which always begins with a comprehensive family history and clinical evaluation. Genetic testing of the proband, the first patient identified in a family with DCM, within the context of genetic counselling is always indicated, regardless of whether the DCM is familial or non-familial. Clinical screening of at-risk family members is also indicated, as is cascade genetic testing for actionable variants found at genetic testing in the proband. Clinicians now have expansive panels with many genes available for DCM genetic testing, and the approaches used to evaluate rare variants to decide which are disease-causing continues to rapidly evolve. Despite these recent advances, only a minority of cases yield actionable variants, even in familial DCM where a genetic aetiology is highly likely. This underscores that our knowledge of DCM clinical genetics remains incomplete, including variant interpretation and DCM genetic architecture. Emerging data suggest that the single-variant Mendelian disease model is insufficient to explain some DCM cases, and rather that multiple variants, both common and rare, and at times key environmental factors, interact to cause DCM. A simple model illustrating the intersection of DCM genetic architecture with environmental impact is provided.

scholarly journals Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0245681
Author(s):  
Juha W. Koskenvuo ◽  
Inka Saarinen ◽  
Saija Ahonen ◽  
Johanna Tommiska ◽  
Sini Weckström ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Dilated Cardiomyopathy ◽  
Molecular Diagnosis ◽  
Reference Population ◽  
Control Group ◽  
Loss Of Function ◽  
Familial Dilated Cardiomyopathy ◽  
Anchoring Protein ◽  
And Control ◽  
Cardiac Group

Background Familial dilated cardiomyopathy (DCM) is typically a monogenic disorder with dominant inheritance. Although over 40 genes have been linked to DCM, more than half of the patients undergoing comprehensive genetic testing are left without molecular diagnosis. Recently, biallelic protein-truncating variants (PTVs) in the nebulin-related anchoring protein gene (NRAP) were identified in a few patients with sporadic DCM. Methods and results We determined the frequency of rare NRAP variants in a cohort of DCM patients and control patients to further evaluate role of this gene in cardiomyopathies. A retrospective analysis of our internal variant database consisting of 31,639 individuals who underwent genetic testing (either panel or direct exome sequencing) was performed. The DCM group included 577 patients with either a confirmed or suspected DCM diagnosis. A control cohort of 31,062 individuals, including 25,912 individuals with non-cardiac (control group) and 5,150 with non-DCM cardiac indications (Non-DCM cardiac group). Biallelic (n = 6) or two (n = 5) NRAP variants (two PTVs or PTV+missense) were identified in 11 unrelated probands with DCM (1.9%) but none of the controls. None of the 11 probands had an alternative molecular diagnosis. Family member testing supports co-segregation. Biallelic or potentially biallelic NRAP variants were enriched in DCM vs. controls (OR 1052, p<0.0001). Based on the frequency of NRAP PTVs in the gnomAD reference population, and predicting full penetrance, biallelic NRAP variants could explain 0.25%-2.46% of all DCM cases. Conclusion Loss-of-function in NRAP is a cause for autosomal recessive dilated cardiomyopathy, supporting its inclusion in comprehensive genetic testing.

scholarly journals Identification of a nonsense mutation in TNNI3K associated with cardiac conduction disease and dilated cardiomyopathy

2019 ◽  
Author(s):  
Jiang Liu ◽  
Da Liu ◽  
Muzheng Li ◽  
Keke Wu ◽  
Na Liu ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Dilated Cardiomyopathy ◽  
Nonsense Mutation ◽  
Underlying Disease ◽  
Cardiac Conduction ◽  
Chinese Family ◽  
Loss Of Function ◽  
Life Threatening ◽  
Next Generation Sequencing Ngs ◽  
Autosomal Dominant Inheritance Pattern

Abstract Background Cardiac conduction disease(CCD) and dilated cardiomyopathy(DCM) are two common cardiovascular diseases which can lead to life-threatening conditions. The importance of heredity in these two diseases has been realized in recent years. Several casual genes have been found to be implicated in CCD and DCM such as LMNA,SCN5A,TTN,TNNI3K and so on. Rare genetic mutations in TNNI3K have been identified to be in connection with CCD and DCM.Methods Next generation sequencing(NGS) was carried out in order to identify the underlying disease-causing mutation in a Chinese family with CCD and DCM. The mutations were validated by Sanger sequencing.Results A nonsense mutation in TNNI3K(NM_015978.2: g.170891C>T,c.1441C>T) was identified in this family and validated by Sanger sequencing.Conclusions This study described a Chinese family with CCD and DCM caused by a nonsense TNNI3K mutation.TNNI3K harboring the mutation(c.1441C>T) possibly implicated a loss-of-function pathogenic mechanism with an autosomal dominant inheritance pattern. This research enriches the phenotypic spectrum of TNNI3K mutations, casting a new light upon the genotype-phenotype correlations between TNNI3K mutations and cardiovascular diseases.

scholarly journals Monomorphic Ventricular Arrhythmias in Athletes

2019 ◽  
Vol 8 (2) ◽  
pp. 83-89 ◽  
Author(s):  
Jeffrey J Hsu ◽  
Ali Nsair ◽  
Jamil A Aboulhosn ◽  
Tamara B Horwich ◽  
Ravi H Dave ◽  
...  
Keyword(s):  
Heart Disease ◽  
Ventricular Arrhythmias ◽  
Comprehensive Evaluation ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Sports Participation ◽  
Structural Heart Disease ◽  
Competitive Sports ◽  
Ventricular Cardiomyopathy ◽  
Electrical Heart Disease ◽  
Increase Risk

Ventricular arrhythmias are challenging to manage in athletes with concern for an elevated risk of sudden cardiac death (SCD) during sports competition. Monomorphic ventricular arrhythmias (MMVA), while often benign in athletes with a structurally normal heart, are also associated with a unique subset of idiopathic and malignant substrates that must be clearly defined. A comprehensive evaluation for structural and/or electrical heart disease is required in order to exclude cardiac conditions that increase risk of SCD with exercise, such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Unique issues for physicians who manage this population include navigating athletes through the decision of whether they can safely continue their chosen sport. In the absence of structural heart disease, therapies such as radiofrequency catheter ablation are very effective for certain arrhythmias and may allow for return to competitive sports participation. In this comprehensive review, we summarise the recommendations for evaluating and managing athletes with MMVA.

scholarly journals Genetic architecture of schizophrenia: a review of major advancements

2021 ◽  
pp. 1-10
Author(s):  
Sophie E. Legge ◽  
Marcos L. Santoro ◽  
Sathish Periyasamy ◽  
Adeniran Okewole ◽  
Arsalan Arsalan ◽  
...  
Keyword(s):  
Genetic Architecture ◽  
Association Studies ◽  
Copy Number Variants ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genetic Loci ◽  
Significant Enrichment ◽  
High Heritability ◽  
Coding Variants

Abstract Schizophrenia is a severe psychiatric disorder with high heritability. Consortia efforts and technological advancements have led to a substantial increase in knowledge of the genetic architecture of schizophrenia over the past decade. In this article, we provide an overview of the current understanding of the genetics of schizophrenia, outline remaining challenges, and summarise future directions of research. World-wide collaborations have resulted in genome-wide association studies (GWAS) in over 56 000 schizophrenia cases and 78 000 controls, which identified 176 distinct genetic loci. The latest GWAS from the Psychiatric Genetics Consortium, available as a pre-print, indicates that 270 distinct common genetic loci have now been associated with schizophrenia. Polygenic risk scores can currently explain around 7.7% of the variance in schizophrenia case-control status. Rare variant studies have implicated eight rare copy-number variants, and an increased burden of loss-of-function variants in SETD1A, as increasing the risk of schizophrenia. The latest exome sequencing study, available as a pre-print, implicates a burden of rare coding variants in a further nine genes. Gene-set analyses have demonstrated significant enrichment of both common and rare genetic variants associated with schizophrenia in synaptic pathways. To address current challenges, future genetic studies of schizophrenia need increased sample sizes from more diverse populations. Continued expansion of international collaboration will likely identify new genetic regions, improve fine-mapping to identify causal variants, and increase our understanding of the biology and mechanisms of schizophrenia.

scholarly journals Catheter Ablation of Life-Threatening Ventricular Arrhythmias in Athletes

Medicina ◽  
2021 ◽  
Vol 57 (3) ◽  
pp. 205
Author(s):  
Nicola Tarantino ◽  
Domenico G. Della Rocca ◽  
Nicole S. De Leon De La Cruz ◽  
Eric D. Manheimer ◽  
Michele Magnocavallo ◽  
...  
Keyword(s):  
Catheter Ablation ◽  
Ventricular Arrhythmias ◽  
Individual Factors ◽  
Substantial Part ◽  
Arrhythmogenic Substrate ◽  
Life Threatening ◽  
History Of ◽  
Anatomic Distribution ◽  
Artery Disease ◽  
Surveillance Analysis

A recent surveillance analysis indicates that cardiac arrest/death occurs in ≈1:50,000 professional or semi-professional athletes, and the most common cause is attributable to life-threatening ventricular arrhythmias (VAs). It is critically important to diagnose any inherited/acquired cardiac disease, including coronary artery disease, since it frequently represents the arrhythmogenic substrate in a substantial part of the athletes presenting with major VAs. New insights indicate that athletes develop a specific electro-anatomical remodeling, with peculiar anatomic distribution and VAs patterns. However, because of the scarcity of clinical data concerning the natural history of VAs in sports performers, there are no dedicated recommendations for VA ablation. The treatment remains at the mercy of several individual factors, including the type of VA, the athlete’s age, and the operator’s expertise. With the present review, we aimed to illustrate the prevalence, electrocardiographic (ECG) features, and imaging correlations of the most common VAs in athletes, focusing on etiology, outcomes, and sports eligibility after catheter ablation.

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