12 results on '"Jenewein T"'
Search Results
2. Genotype-phenotype dilemma in a case of sudden cardiac death with the E1053K mutation and a deletion in the SCN5A gene
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Jenewein, T., Beckmann, B.M., Rose, S., Osterhues, H.H., Schmidt, U., Wolpert, C., Miny, P., Marschall, C., Alders, M., Bezzina, C.R., Wilde, A.A.M., Kääb, S., and Kauferstein, S.
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- 2017
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3. "Re-evaluation of variants of uncertain significance in patients with hereditary arrhythmogenic disorders".
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Martin S, Jenewein T, Geisen C, Scheiper-Welling S, and Kauferstein S
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- Humans, Heredity, Risk Assessment, Risk Factors, Databases, Genetic, Genetic Predisposition to Disease, Arrhythmias, Cardiac genetics, Arrhythmias, Cardiac diagnosis, Genetic Testing, Phenotype, High-Throughput Nucleotide Sequencing, Predictive Value of Tests, Genetic Variation
- Abstract
Background: Genetic diagnostics support the diagnosis of hereditary arrhythmogenic diseases, but variants of uncertain significance (VUS) complicate matters, emphasising the need for regular reassessment. Our study aims to reanalyse rare variants in different genes in order to decrease VUS diagnoses and thus improve risk stratification and personalized treatment for patients with arrhythmogenic disorders., Methods: Genomic DNA was analysed using Sanger sequencing and next-generation sequencing (NGS). The Data was evaluated using various databases and in silico prediction tools and classified according to current ACMG standards by two independent experts., Results: We identified 53 VUS in 30 genes, of which 17 variants (32%) were reclassified. 13% each were downgraded to likely benign (LB) and benign (B) and 6% were upgraded to likely pathogenic (LP). Reclassifications mainly occurred among variants initially classified in 2017-2019, with rates ranging from 50 to 60%., Conclusion: The results support the assumption that regular reclassification of VUS is important, as it provides new insights for genetic diagnostics, that benefit patients and guide therapeutic approach., (© 2024. The Author(s).)
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- 2024
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4. From rare events to systematic data collection: the RESCUED registry for sudden cardiac death in the young in Germany.
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Barkauskas R, Jenewein T, Scheiper-Welling S, Wilmes V, Niess C, Petzel-Witt S, Reitz A, Gradhand E, Falagkari A, Papathanasiou M, Wakili R, Leistner DM, Vasseur J, Göbel J, Storf H, Toennes SW, Kettner M, Verhoff MA, Beckmann BM, Kauferstein S, and Corvest E
- Abstract
Background: Approximately one-third of sudden cardiac deaths in the young (SCDY) occur due to a structural cardiac disease. Forty to fifty percent of SCDY cases remain unexplained after autopsy (including microscopic and forensic-toxicological analyses), suggesting arrhythmia syndromes as a possible cause of death. Due to the possible inheritability of these diseases, blood relatives of the deceased may equally be carriers of the causative genetic variations and therefore may have an increased cardiac risk profile. A better understanding of the forensic, clinical, and genetic data might help identify a subset of the general population that is at increased risk of sudden cardiac death., Study Design: The German registry RESCUED (REgistry for Sudden Cardiac and UnExpected Death) comprises information about SCDY fatalities and clinical and genetic data of both the deceased and their biological relatives. The datasets collected in the RESCUED registry will allow for the identification of leading causes of SCDY in Germany and offer unique possibilities of scientific analyses with the aim of detecting unrecognized trends, risk factors, and clinical warning signs of SCDY. In a pilot phase of 24 months, approximately 180 SCDY cases (< 50 years of age) and 500 family members and clinical patients will be included., Conclusion: RESCUED is the first registry in Germany collecting comprehensive data of SCDY cases and clinical data of the biological relatives reviewed by cardiac experts. RESCUED aims to improve individual risk assessment and public health approaches by directing resources towards early diagnosis and evidence-based, personalized therapy and prevention in affected families. Trial registration number (TRN): DRKS00033543., (© 2024. The Author(s).)
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- 2024
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5. Telemedical monitoring in patients with inborn cardiac disease - experience of a tertiary care centre.
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Westphal DS, Federle D, Steger A, Vodermeier T, Scheiper-Welling S, Jenewein T, Beckmann BM, Kauferstein S, Martens E, and Hahn F
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- Humans, Tertiary Care Centers, Arrhythmias, Cardiac diagnosis, Arrhythmias, Cardiac genetics, Heart, Defibrillators, Implantable adverse effects, Telemedicine
- Abstract
Background: The number of cardiologically relevant genetic findings will continue to increase. This is due to the use of high-throughput sequencing techniques and the critical role of incidental findings in cardiac disease genes. Telemedicine can be a useful diagnostic tool to monitor the heart rhythm of patients with inborn cardiac diseases., Methods: Patients were screened once they had been referred to our outpatient department for rare cardiac diseases between January 2020 and May 2022. Those patients who underwent genetic testing and were consequently diagnosed with a genetic disorder were included in this study. Their medical records were evaluated regarding implanted cardiac electronic devices and findings in the telemedical monitoring., Results: 304 patients were seen in our outpatient department for rare cardiac diseases in the mentioned period. In 100 cases, genetic testing was performed. 10 patients (10%) with an identified inborn cardiac disease were monitored via telemedicine until the end of May 2022. 4 patients were monitored by implantable loop recorders (ILR), 4 patients were monitored by Implantable Cardioverter Defibrillators (ICD), and 2 patients received both devices. Clinical relevant arrhythmias making medical intervention necessary were identified in 4 cases. In two cases, data interpretation was hampered by sinus tachycardia caused by physical exercise., Discussion: Telemonitoring of the heart rhythm by medical devices is beneficial for patients with monogenic heart diseases. Especially, when the indication for an ICD is not clear, implantation of a telemonitored ILR can be a suitable choice. However, rhythm analysis can be challenging in young patients who are physically active., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2023
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6. Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome KCNQ1 Variants.
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Rinné S, Oertli A, Nagel C, Tomsits P, Jenewein T, Kääb S, Kauferstein S, Loewe A, Beckmann BM, and Decher N
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- Humans, KCNQ1 Potassium Channel genetics, Phenotype, Electrocardiography, Mutation, KCNQ Potassium Channels genetics, Romano-Ward Syndrome genetics, Jervell-Lange Nielsen Syndrome genetics
- Abstract
The KCNQ1 gene encodes the α-subunit of the cardiac voltage-gated potassium (Kv) channel KCNQ1, also denoted as Kv7.1 or KvLQT1. The channel assembles with the ß-subunit KCNE1, also known as minK, to generate the slowly activating cardiac delayed rectifier current I
Ks , a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function variants in KCNQ1 cause the congenital Long QT1 (LQT1) syndrome, characterized by delayed cardiac repolarization and a QT interval prolongation in the surface electrocardiogram (ECG). Autosomal dominant loss-of-function variants in KCNQ1 result in the LQT syndrome called Romano-Ward syndrome (RWS), while autosomal recessive variants affecting function, lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. The aim of this study was the characterization of novel KCNQ1 variants identified in patients with RWS to widen the spectrum of known LQT1 variants, and improve the interpretation of the clinical relevance of variants in the KCNQ1 gene. We functionally characterized nine human KCNQ1 variants using the voltage-clamp technique in Xenopus laevis oocytes, from which we report seven novel variants. The functional data was taken as input to model surface ECGs, to subsequently compare the functional changes with the clinically observed QTc times, allowing a further interpretation of the severity of the different LQTS variants. We found that the electrophysiological properties of the variants correlate with the severity of the clinically diagnosed phenotype in most cases, however, not in all. Electrophysiological studies combined with in silico modelling approaches are valuable components for the interpretation of the pathogenicity of KCNQ1 variants, but assessing the clinical severity demands the consideration of other factors that are included, for example in the Schwartz score.- Published
- 2023
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7. Variant interpretation in molecular autopsy: a useful dilemma.
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Scheiper-Welling S, Tabunscik M, Gross TE, Jenewein T, Beckmann BM, Niess C, Gradhand E, Wunder C, Schneider PM, Rothschild MA, Verhoff MA, and Kauferstein S
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- Adolescent, Autopsy, Cohort Studies, High-Throughput Nucleotide Sequencing, Humans, Young Adult, Death, Sudden, Cardiac etiology, Genetic Testing
- Abstract
Sudden cardiac death (SCD) in adolescents and young adults may be the first manifestation of an inherited arrhythmic syndrome. Thus identification of a genetic origin in sudden death cases deemed inconclusive after a comprehensive autopsy and may help to reduce the risk of lethal episodes in the remaining family. Using next-generation sequencing (NGS), a large number of variants of unknown significance (VUS) are detected. In the majority of cases, there is insufficient evidence of pathogenicity, representing a huge dilemma in current genetic investigations. Misinterpretation of such variants may lead to inaccurate genetic diagnoses and/or the adoption of unnecessary and/or inappropriate therapeutic approaches. In our study, we applied current (ACMG) recommendations for variant classification in post-mortem genetic screening of a cohort of 56 SCD victims. We identified a total 53 rare protein-altering variants (MAF < 0.2%) classified as VUS or worse. Twelve percent of the cases exhibited a clinically actionable variant (pathogenic, likely pathogenic or VUS - potentially pathogenic) that would warrant cascade genetic screening in relatives. Most of the variants detected by means of the post-mortem genetic investigations were VUS. Thus, genetic testing by itself might be fairly meaningless without supporting background data. This data reinforces the need for an experienced multidisciplinary team for obtaining reliable and accountable interpretations of variant significance for elucidating potential causes for SCDs in the young. This enables the early identification of relatives at risk or excludes family members as genetic carriers. Also, development of adequate forensic guidelines to enable appropriate interpretation of rare genetic variants is fundamental., (© 2021. The Author(s).)
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- 2022
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8. The mutation L69P in the PAS domain of the hERG potassium channel results in LQTS by trafficking deficiency.
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Jenewein T, Kanner SA, Bauer D, Hertel B, Colecraft HM, Moroni A, Thiel G, and Kauferstein S
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- Adult, Female, Flow Cytometry, Humans, Microscopy, Confocal, Protein Transport genetics, Protein Transport physiology, ERG1 Potassium Channel genetics, Long QT Syndrome genetics, Mutation genetics
- Abstract
The congenital long QT syndrome (LQTS) is a cardiac disorder characterized by a prolonged QT interval on the electrocardiogram and an increased susceptibility to ventricular arrhythmias and sudden cardiac death. A frequent cause for LQTS is mutations in the KCNH2 gene (also known as the human ether-a-go-go-related gene or hERG ), which reduce or modulate the potassium current I
Kr and hence alter cardiac repolarization. In a patient with a clinically diagnosed LQTS, we identified the mutation L69P in the N-terminal PAS (Per-Arnt-Sim) domain of hERG. Functional expression in HEK293 cells shows that a homotetrameric hERG channel reconstituted with only mutant subunits exhibits a drastically reduced surface expression of the channel protein thus leading to a diminished hERG current. Unlike many other mutations in the hERG-PAS domain the negative impact of the L69P substitution cannot be rescued by facilitated protein folding at a lower incubation temperature. Further, co-expression of wt and mutant monomers does not restore either wt like surface expression or the full hERG current. These results indicate L69P is a dominant negative mutation, with deficits which most likely occurs at the level of protein folding and subsequently inhibits trafficking to the plasma membrane. The functional deficits of the mutant channel support the clinical diagnosis of a LQTS.- Published
- 2020
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9. Brother-brother or father-son? How a dropout of AmelX may facilitate the elucidation of a familial relationship.
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Zajac BK, Scheiper S, Zehner R, Jenewein T, and Weissenberger M
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- DNA Primers, Fathers, Humans, Male, Microsatellite Repeats, Pakistan ethnology, Sequence Analysis, DNA, Siblings, Alleles, Amelogenin genetics, DNA isolation & purification, Forensic Genetics
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- 2020
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10. Influence of genetic modifiers on sudden cardiac death cases.
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Jenewein T, Neumann T, Erkapic D, Kuniss M, Verhoff MA, Thiel G, and Kauferstein S
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- Adolescent, Adult, Amino Acid Substitution, Exons, Female, Gene Frequency, Heterozygote, Humans, Long QT Syndrome genetics, Mutation, Pedigree, Polymorphism, Genetic, Death, Sudden, Cardiac etiology, ERG1 Potassium Channel genetics, NAV1.5 Voltage-Gated Sodium Channel genetics
- Abstract
Sequence variants in the ion channel genes KCNH2 and SCN5A may cause the cardiac disorder long QT syndrome (LQTS). This disorder is associated with incomplete penetrance and variable expression in KCNH2- or SCN5A-mutation carriers. Common genetic variants, if associated with a mutation, may affect the severity of this cardiac disorder. This study identified rare mutations in the cardiac ion channel genes KCNH2 and SCN5A in a SCD case, as well as in a LQTS-affected family with a history of SCD. Moreover, common variants were found to occur together within the same genes. These findings support the concept that common single-nucleotide polymorphisms (SNPs) in genes encoding cardiac ion channels can directly modulate the functional effect of mutations and therefore enhance or weaken the risk of cardiac events.
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- 2018
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11. Relevance of molecular testing in patients with a family history of sudden death.
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Kauferstein S, Herz N, Scheiper S, Biel S, Jenewein T, Kunis M, Erkapic D, Beckmann BM, and Neumann T
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- Adult, Arrhythmias, Cardiac diagnosis, Female, Genetic Variation, Heart Diseases complications, Humans, Male, Mutation, Arrhythmias, Cardiac genetics, Death, Sudden, Cardiac etiology, Family, Genetic Predisposition to Disease, Genetic Testing
- Abstract
Sudden cardiac death (SCD) is a major cause of death in industrial countries. Although SCD occurs mainly in adults, it may also affect young persons, where genetic cardiac disorders comprise at least half of these cases. This includes primary arrhythmogenic disorders such as long QT syndrome and inherited cardiomyopathies. However, in many cases, postmortem examinations provide no conclusive results explaining the cause of death. Since family members of the deceased may eventually have inherited the same disease, they are at risk of SCD. In the present study, 28 patients with a family history of sudden unexplained death (SUD), of survived cardiac arrest and with a clinical diagnosis of an inherited cardiac disease were screened using phenotype-guided molecular analysis of genes associated with arrhythmogenic cardiac diseases. In 64% of the cases, gene variants with potentially pathogenic cardiac effects were detected suggesting that an arrhythmia syndrome may have caused the death of the deceased family member. Therefore, we recommend that relatives of SUD victims should undergo extended cardiac examination and, depending on the clinical diagnosis, a targeted genetic analysis should follow, which is crucial to identify family members at risk., (Copyright © 2017 Elsevier B.V. All rights reserved.)
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- 2017
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12. Genetic analysis of sudden unexplained death: a multidisciplinary approach.
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Kauferstein S, Kiehne N, Jenewein T, Biel S, Kopp M, König R, Erkapic D, Rothschild M, and Neumann T
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- Adolescent, Adult, Arrhythmias, Cardiac genetics, Cooperative Behavior, Female, Forensic Genetics, Genetic Counseling, Humans, Male, Pedigree, Young Adult, Death, Sudden, Cardiac etiology, Genetic Testing, Mutation, NAV1.5 Voltage-Gated Sodium Channel genetics, Potassium Channels, Inwardly Rectifying genetics, Ryanodine Receptor Calcium Release Channel genetics
- Abstract
Each year infants, children and young adults die suddenly and unexpectedly. In many cases the cause of death can be elucidated by medico-legal autopsy, however, a significant number of these cases remain unexplained despite a detailed postmortem investigation and are labeled as sudden unexplained death (SUD). Post-mortem genetic testing, so called molecular autopsy, revealed that primary arrhythmogenic disorders including long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT) may account for a certain number of these cases. Because of the inheritance of these diseases, close relatives of the deceased may also at potential risk of carrying fatal cardiac disorders. Therefore, advanced diagnostic analyses, genetic counseling and interdisciplinary collaboration should be integral parts of clinical and forensic practice. In the present study, we performed mutation analyses of the major genes causing cardiac channelopathies in 15 SUD cases. In four cases we found putative pathogenic mutations in cardiac ion channel genes. Clinical and genetic examination of family members of SUD victims was also performed and affected family members were identified. This study demonstrates that molecular genetic screening needs to become an inherent part of the postmortem examination. This will enhance the ability of screening family members of SUD victims who may be at risk. The present data also illustrate that detection and follow up of familial cases of sudden death is challenging and requires a close multidisciplinary collaboration between different medical disciplines, with great responsibility for the forensic pathologist., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)
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- 2013
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