Genotype-Phenotype Correlation: A Triple DNA Mutational Event in a Boy Entering Sport Conveys an Additional Pathogenicity Risk

The purpose of this paper is to present a clinical and laboratory study of a family, in which a 12-year-old boy was examined to assess his health status before starting competitive sports. A variety of clinical and instrumental tests were used to evaluate the status of the heart and its functions. Using Sanger sequencing (SS), we sequenced six related genes to verify suspected arrhythmogenic right ventricular cardiomyopathy (ARVC) hypothesized at the cardiac assessment and, subsequently, by a next-generation sequencing (NGS)-based multi-gene panel for more paramount genetic risk of sudden cardiac death (SCD) assessment. SS revealed two variants in the PKP2 gene, one was inherited from the father and the other from the mother. The analysis on a large panel of genes (n = 138), putatively associated with sudden cardiac death, revealed, in the proband, a third variant in a different gene (DES) that encodes the protein desmin. Our results indicate that: i) NGS revealed a mutational event in a gene not conventionally screened as a first-line test in the presence of clinical suspicion of the arrhythmic disease; ii) a plurality of variants in different genes in the same subject (the proband) may increase the risk of heart disease; iii) in silico analysis with various methodological software and bioinformatic prediction tools indicates that the cumulative effects of the three variants in the same subject constitute an additional risk factor. This case report indicates that more pathogenic variants or likely pathogenic variants can contribute to the clinical phenotype of an individual, thereby contributing to the diagnosis and prognosis of inherited heart diseases.

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Implantable Cardioverter–Defibrillators for Primary Prevention of Sudden Cardiac Death

European Cardiology Review ◽

10.15420/ecr.2010.6.3.92 ◽

2010 ◽

Vol 6 (3) ◽

pp. 92

Author(s):

Felix Gramley ◽

Andreas Goette ◽

◽

Keyword(s):

Primary Prevention ◽

High Risk ◽

Sudden Cardiac Death ◽

Cardiac Death ◽

Heart Diseases ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Polymorphic Ventricular Tachycardia ◽

Implantable Cardioverter Defibrillators ◽

Qt Syndrome ◽

Cardioverter Defibrillators

Sudden cardiac death (SCD) remains a major cause of death in the industrialised world. Implantable cardioverter–defibrillators (ICDs) have been shown to be an effective therapy option for the primary prevention of SCD in patients at high risk of SCD. This review will discuss adequate risk stratification in various disease states, such as coronary artery disease, ischaemic and non-ischaemic cardiomyopathies (dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy), channelopathies (Brugada syndrome, long- QT syndrome, short-QT syndrome, catecholaminergic polymorphic ventricular tachycardia) and congenital heart diseases, to identify patients at high risk of SCD and selection criteria for ICD therapy. The most important clinical primary prevention trials will be highlighted. Finally, complications of device therapy and quality of life issues will be addressed.

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Functional characterization of novel alpha-helical rod domain desmin (DES) pathogenic variants associated with dilated cardiomyopathy, atrioventricular block and a risk for sudden cardiac death

International Journal of Cardiology ◽

10.1016/j.ijcard.2020.12.050 ◽

2020 ◽

Author(s):

Björn Fischer ◽

Sven Dittmann ◽

Andreas Brodehl ◽

Andreas Unger ◽

Birgit Stallmeyer ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Dilated Cardiomyopathy ◽

Atrioventricular Block ◽

Cardiac Death ◽

Functional Characterization ◽

Pathogenic Variants

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The first reported case of arrhythmogenic right ventricular cardiomyopathy in a horse as cause of sudden cardiac death in the USA

Journal of Comparative Pathology ◽

10.1016/j.jcpa.2018.10.123 ◽

2019 ◽

Vol 166 ◽

pp. 138

Author(s):

I. Erdélyi ◽

J. Keating

Keyword(s):

Sudden Cardiac Death ◽

Right Ventricular ◽

Cardiac Death ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Ventricular Cardiomyopathy ◽

The Usa

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First nationwide study of sudden cardiac death due to arrhythmogenic right ventricular cardiomyopathy in the young; fifty percent have symptoms prior to death

European Heart Journal ◽

10.1093/eurheartj/eht309.3771 ◽

2013 ◽

Vol 34 (suppl 1) ◽

pp. 3771-3771

Author(s):

G. Golnaz ◽

R. Jabbari ◽

B. Risgaard ◽

M. S. Olesen ◽

S. Haunsoe ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Right Ventricular ◽

Cardiac Death ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Ventricular Cardiomyopathy ◽

Nationwide Study

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P859 Can we connect intraventricular exercise induced gradients to sudden cardiac death?

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jez319.504 ◽

2020 ◽

Vol 21 (Supplement_1) ◽

Author(s):

C Cotrim ◽

F Costa ◽

D Severino ◽

L Baquero ◽

J Guardado

Keyword(s):

Sudden Cardiac Death ◽

Cardiac Death ◽

Heart Diseases ◽

Young Male ◽

Exercise Stress ◽

Male Athlete ◽

First Case ◽

History Of ◽

Intense Training ◽

Exercise Induced

Abstract Background Some publications, on exercise induced intraventricular gradients, admit the possibility they can be related to some cases of unexplained sudden cardiac death (SCD). Clinical case We present the case of a young male athlete (16 years) that after winning a triathlon competition has sudden cardiac death. No cardiovascular risk factors. No family history of SCD A previous episode of dizziness, accompanied by nausea and vomiting related to intense training happens 6 months before. In September 2018 about 30 minutes after winning a triathlon competition has SCD episode having been resuscitated on site by the competition physician having been defibrillated and transported to intensive care unit. After discharge, cardiac MRI, Coronary AngioTC, complete genetic study for heart diseases, flecainid test, transthoracic echocardiogram, stress echocardiogram with hyperventilation and ergometrine. All have normal results (Figure) During 24 hours Holter ECG isolated premature ventricular complexes were detected and during exercise stress echocardiography a significant intraventricular gradient without systolic anterior movement of mitral valve was detected (Figure). The athlete was disqualified for sports practice, refuses CDI implantation and started bisoprolol 2,5 mg daily. To the best of our knowledge this is the first case of association between SCD and exercise induced intraventricular gradient. This possible association should be studied in the future. Abstract P859 Figure. Intraventricular gradient in SCD athlete

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P1392Next generation sequencing in lone atrial fibrillation patients

EP Europace ◽

10.1093/europace/euaa162.320 ◽

2020 ◽

Vol 22 (Supplement_1) ◽

Author(s):

I Rudaka ◽

D Rots ◽

O Kalejs ◽

L Gailite

Keyword(s):

Atrial Fibrillation ◽

Sudden Cardiac Death ◽

Genetic Variants ◽

Cardiac Death ◽

Structural Heart Disease ◽

Missense Variant ◽

Lone Atrial Fibrillation ◽

Excessive Alcohol Consumption ◽

Pathogenic Variants ◽

Rare Genetic Variants

Abstract Background. Minor part of atrial fibrillation (AF) patients develops the disease without any well-known risk factors, which is a particular form of the disease, known as a lone AF. Rare genetic variants were described as causative for lone AF. The aim of this study was to investigate occurrence of rare genetic variants in lone AF patients. Material and Methods. We performed Mendeliome sequencing for 21 lone AF patients. Lone AF was defined as AF in individuals younger than 65 years in the absence of cardiovascular or structural heart disease, endocrinologic or pulmonary disease, chronic kidney disease, obesity and excessive alcohol consumption. Data analysis was performed by current laboratory pipeline. We analyzed 453 cardiomyopathy, arrhythmias and sudden cardiac death related genes. Results. In eight out of 21 (38%) lone AF patients rare likely pathogenic variants were found (Table 1.). Seven rare truncating TTN variants and one LMNA missense variant were observed. Four unrelated patients were positive for the same TTN variant c.13696 C > T; p.(Gln4566Ter). The same variant was previously found in ARVC patient in our laboratory. Segregation analysis and phenotyping of relatives is ongoing. Conclusions. Rare genetic variants are common causes of the lone atrial fibrillation. TTN gene variant c.13696C > T; p.(Gln4566Ter) is a potential founder variant in the Baltic population. Table 1. Genetic variants in lone AF Gender Age of AF onset Genetic variant Family history Male 53 LMNA: p.(Ser326Thr) AF in mother Male 11 TTN: p.(Trp31854Ter) AF in father Male 30 TTN: p.(GLn4566Ter) AF in uncle Female 45 TTN: p.(GLn4566Ter) Negative Male 37 TTN: p.(GLn4566Ter) AF in father Male 25 TTN: p.(GLn4566Ter) AF in father, maternal and paternal grandmother Female 60 TTN: p.(Arg27414Ter) Sudden cardiac death at the age of 50 in grand father Female 52 TTN: p.(Arg1012Ter) AF in mother

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Integrin β1D Deficiency–Mediated RyR2 Dysfunction Contributes to Catecholamine-Sensitive Ventricular Tachycardia in Arrhythmogenic Right Ventricular Cardiomyopathy

Circulation ◽

10.1161/circulationaha.119.043504 ◽

2020 ◽

Vol 141 (18) ◽

pp. 1477-1493 ◽

Cited By ~ 3

Author(s):

Yihui Wang ◽

Chunyan Li ◽

Ling Shi ◽

Xiuyu Chen ◽

Chen Cui ◽

...

Keyword(s):

Ventricular Tachycardia ◽

Sudden Cardiac Death ◽

Right Ventricular ◽

Cardiac Death ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Left Ventricular ◽

Polymorphic Ventricular Tachycardia ◽

Ventricular Cardiomyopathy ◽

Open Probability ◽

Increased Risk

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary heart disease characterized by fatty infiltration, life-threatening arrhythmias, and increased risk of sudden cardiac death. The guideline for management of ARVC in patients is to improve quality of life by reducing arrhythmic symptoms and to prevent sudden cardiac death. However, the mechanism underlying ARVC-associated cardiac arrhythmias remains poorly understood. Methods: Using protein mass spectrometry analyses, we identified that integrin β1 is downregulated in ARVC hearts without changes to Ca 2+ -handling proteins. As adult cardiomyocytes express only the β1D isoform, we generated a cardiac specific β1D knockout mouse model and performed functional imaging and biochemical analyses to determine the consequences of integrin β1D loss on function in the heart in vivo and in vitro. Results: Integrin β1D deficiency and RyR2 Ser-2030 hyperphosphorylation were detected by Western blotting in left ventricular tissues from patients with ARVC but not in patients with ischemic or hypertrophic cardiomyopathy. Using lipid bilayer patch clamp single channel recordings, we found that purified integrin β1D protein could stabilize RyR2 function by decreasing RyR2 open probability, mean open time, and increasing mean close time. Also, β1D knockout mice exhibited normal cardiac function and morphology but presented with catecholamine-sensitive polymorphic ventricular tachycardia, consistent with increased RyR2 Ser-2030 phosphorylation and aberrant Ca 2+ handling in β1D knockout cardiomyocytes. Mechanistically, we revealed that loss of DSP (desmoplakin) induces integrin β1D deficiency in ARVC mediated through an ERK1/2 (extracellular signal–regulated kinase 1 and 2)–fibronectin–ubiquitin/lysosome pathway. Conclusions: Our data suggest that integrin β1D deficiency represents a novel mechanism underlying the increased risk of ventricular arrhythmias in patients with ARVC.

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Cardiac phenotype in ATP1A3-related syndromes

Neurology ◽

10.1212/wnl.0000000000010794 ◽

2020 ◽

Vol 95 (21) ◽

pp. e2866-e2879

Author(s):

Simona Balestrini ◽

Mohamad A. Mikati ◽

Reyes Álvarez-García-Rovés ◽

Michael Carboni ◽

Arsen S. Hunanyan ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Cardiac Death ◽

Rapid Onset ◽

Conduction Delay ◽

Conduction Abnormality ◽

Alternating Hemiplegia Of Childhood ◽

Cardiac Phenotype ◽

Sequence Of Events ◽

Cardiac Assessment ◽

Life Threatening

ObjectiveTo define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes.MethodsPatients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/−) to determine the sequence of events in seizure-related cardiac death.ResultsNinety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death.ConclusionsWe found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

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Arrhythmogenic right ventricular cardiomyopathy or athlete's heart? Challenges in assessment of right heart morphology and function

Monaldi Archives for Chest Disease ◽

10.4081/monaldi.2019.1047 ◽

2019 ◽

Vol 89 (1) ◽

Author(s):

Francesco Antonini-Canterin ◽

Concetta Di Nora

Keyword(s):

Sudden Cardiac Death ◽

Right Ventricular ◽

Cardiac Death ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Ventricular Cardiomyopathy ◽

Young Athletes ◽

Right Heart ◽

Lack Of Information ◽

And Function ◽

Athlete's Heart

The incidence of sudden cardiac death (SCD) in young athletes varies among studies, due to the disagreement in the definitions and the lack of information in this field.

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