Abstract
Aims
The early repolarization syndrome (ERS) can cause ventricular fibrillation (VF) and sudden death in young, otherwise healthy individuals. There are limited data suggesting that ERS ...might be heritable. The aim of this study was to characterize the clinical phenotype and to identify a causal variant in an affected family using an exome-sequencing approach.
Methods and results
Early repolarization syndrome was diagnosed according to the recently proposed Shanghai ERS Score. After sequencing of known ERS candidate genes, whole-exome sequencing (WES) was performed. The index patient (23 years, female) showed a dynamic inferolateral early repolarization (ER) pattern and electrical storm with intractable VF. Isoproterenol enabled successful termination of electrical storm with no recurrence on hydroquinidine therapy during 33 months of follow-up. The index patient’s brother (25 years) had a persistent inferior ER pattern with malignant features and a history of syncope. Both parents were asymptomatic and showed no ER pattern. While there was no pathogenic variant in candidate genes, WES detected a novel missense variant affecting a highly conserved residue (p. H2245R) in the ANK3 gene encoding Ankyrin-G in the two siblings and the father.
Conclusion
We identified two siblings with a malignant ERS phenotype sharing a novel ANK3 variant. A potentially pathogenic role of the novel ANK3 variant is suggested by the direct interaction of Ankyrin-G with the cardiac sodium channel, however, more patients with ANK3 variants and ERS would be required to establish ANK3 as novel ERS susceptibility gene. Our study provides additional evidence that ERS might be a heritable condition.
Pediatric cardiomyopathy is a rare but severe disease with high morbidity and mortality. The causes are poorly understood and can only be established in one-third of cases. Recent advances in genetic ...technologies, specifically next-generation sequencing, now allow for the detection of genetic causes of cardiomyopathy in a systematic and unbiased manner. This is particularly important given the large clinical variability among pediatric cardiomyopathy patients and the large number of genes (>100) implicated in the disorder. We report on the performance of whole-exome sequencing in members of a consanguineous family with a history of pediatric hypertrophic cardiomyopathy and sudden cardiac death, which led to the identification of a homozygous stop variant in the SLC22A5 gene, implicated in primary carnitine deficiency, as the likely genetic cause. Targeted carnitine tandem mass spectrometry analysis in the patient revealed complete absence of plasma-free carnitine and only trace levels of total carnitine, further supporting the causality of the SLC22A5 variant. l-carnitine supplementation in the proband led to a rapid and marked clinical improvement. This case illustrates the use of exome sequencing as a systematic and unbiased diagnostic tool in pediatric cardiomyopathy, providing an efficient route to the identification of the underlying cause, which lead to appropriate treatment and prevention of premature death.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Five families were identified with a novel autosomal dominant syndrome characterized by marked ST-segment depression, the development of atrial fibrillation and ventricular arrhythmias, and (in older ...persons) left ventricular dysfunction.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disorder characterized by fibro-fatty replacement of cardiomyocytes. The cardinal manifestations are arrhythmias, sudden ...cardiac death, and seldom heart failure. Mutations in genes encoding desmosomal proteins and their interaction partners have been implicated in the pathogenesis of ARVC and it is now widely accepted that ARVC is a disease caused by abnormal cell-cell adhesion. The mechanism(s) by which mutations in desmosomal proteins lead to fibro-fatty replacement remains to be fully elucidated. To this aim over the last 10 years different transgenic and targeted mouse models have been developed, these models and what they have taught us will be discussed in this review.
The first human mutations in GATA6 were described in a cohort of patients with persistent truncus arteriosus, and the phenotypic spectrum has expanded since then. This study underscores the broad ...phenotypic spectrum by presenting two patients with de novo GATA6 mutations, both exhibiting complex cardiac defects, pancreatic, and other abnormalities. Furthermore, we provided a detailed overview of all published human genetic variation in/near GATA6 published to date and the associated phenotypes (n = 78). We conclude that the most common phenotypes associated with a mutation in GATA6 were structural cardiac and pancreatic abnormalities, with a penetrance of 87 and 60%, respectively. Other common malformations were gallbladder agenesis, congenital diaphragmatic hernia, and neurocognitive abnormalities, mostly developmental delay. Fifty‐eight percent of the mutations were de novo, and these patients more often had an anomaly of intracardiac connections, an anomaly of the great arteries, and hypothyroidism, compared with those with inherited mutations. Functional studies mostly support loss‐of‐function as the pathophysiological mechanism. In conclusion, GATA6 mutations give a wide range of phenotypic defects, most frequently malformations of the heart and pancreas. This highlights the importance of detailed clinical evaluation of identified carriers to evaluate their full phenotypic spectrum.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
IntroductionEarly recognition of individuals with increased risk of sudden cardiac arrest (SCA) remains challenging. SCA research so far has used data from cardiologist care, but missed most SCA ...victims, since they were only in general practitioner (GP) care prior to SCA. Studying individuals with type 2 diabetes (T2D) in GP care may help solve this problem, as they have increased risk for SCA, and rich clinical datasets, since they regularly visit their GP for check-up measurements. This information can be further enriched with extensive genetic and metabolic information.AimTo describe the study protocol of the REcognition of Sudden Cardiac arrest vUlnErability in Diabetes (RESCUED) project, which aims at identifying clinical, genetic and metabolic factors contributing to SCA risk in individuals with T2D, and to develop a prognostic model for the risk of SCA.MethodsThe RESCUED project combines data from dedicated SCA and T2D cohorts, and GP data, from the same region in the Netherlands. Clinical data, genetic data (common and rare variant analysis) and metabolic data (metabolomics) will be analysed (using classical analysis techniques and machine learning methods) and combined into a prognostic model for risk of SCA.ConclusionThe RESCUED project is designed to increase our ability at early recognition of elevated SCA risk through an innovative strategy of focusing on GP data and a multidimensional methodology including clinical, genetic and metabolic analyses.
Abstract We present a family from a founder population referred to cardiogenetic evaluation for atrioventricular block in three siblings. Genetic testing including whole-exome sequencing did not ...identify a disease-causing mutation. After reconsidering the differential diagnosis, a non-genetic cause was identified. This case highlights the importance of a thorough clinical evaluation even when a genetic etiology is seemingly obvious.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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