scholarly journals Pediatric Malignant Arrhythmias Caused by Rare Homozygous Genetic Variants in TRDN: A Comprehensive Interpretation

2021 ◽  
Vol 8 ◽  
Author(s):  
Georgia Sarquella-Brugada ◽  
Anna Fernandez-Falgueras ◽  
Sergi Cesar ◽  
Elena Arbelo ◽  
Paloma Jordà ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Rare Variants ◽  
Early Recognition ◽  
Hot Spot ◽  
Pediatric Population ◽  
Specific Area ◽  
Implantable Defibrillator ◽  
Genetic Alterations ◽  
Malignant Arrhythmias ◽  
Genotype Correlation

Aim: To perform a comprehensive phenotype-genotype correlation of all rare variants in Triadin leading to malignant arrhythmias in pediatrics.Methods: Triadin knockout syndrome is a rare entity reported in pediatric population. This syndrome is caused by rare variants in the TRDN gene. Malignant ventricular arrhythmias and sudden cardiac death can be a primary manifestation of disease. Although pharmacological measures are effective, some patients require an implantable defibrillator due to high risk of arrhythmogenic episodes.Main Results: Fourteen rare genetic alterations in TRDN have been reported to date. All of these potentially pathogenic alterations are located in a specific area of TRDN, highlighting this hot spot as an arrhythmogenic gene region.Conclusions: Early recognition and comprehensive interpretation of alterations in Triadin are crucial to adopt preventive measures and avoid malignant arrhythmogenic episodes in pediatric population.

scholarly journals Fulminant Myocarditis: Brief Review

2021 ◽  
Vol 3 (3) ◽  
pp. 01-04
Author(s):  
Ezra A Amsterdam ◽  
Muhammad Majid
Keyword(s):  
Heart Transplantation ◽  
Cardiac Imaging ◽  
Ventricular Arrhythmias ◽  
Early Recognition ◽  
Standard Test ◽  
Fulminant Myocarditis ◽  
Myocardial Inflammation ◽  
Aggressive Management ◽  
Hemodynamic Impairment ◽  
Malignant Arrhythmias

Fulminant myocarditis (FM) is a rare disease characterized by acute hemodynamic impairment and ventricular arrhythmias due to severe myocardial inflammation. It is typically preceded by a viral infection but any of multiple other toxic and infective agents may also be the inciting agent. Diagnosis is based on biomarkers and/or cardiac imaging, but endomyocardial biopsy is the standard test for confirming the diagnosis. FM usually requires therapeutic support of cardiac function and treatment of malignant arrhythmias. Contrary to prior concepts, recent evidence has revealed that patients with FM are more likely to die or need heart transplantation than those with the nonfulminant form of the disease. Early recognition and aggressive management are essential for favorable outcomes.

scholarly journals Malignant Arrhythmogenic Role Associated with RBM20: A Comprehensive Interpretation Focused on a Personalized Approach

2021 ◽  
Vol 11 (2) ◽  
pp. 130
Author(s):  
Paloma Jordà ◽  
Rocío Toro ◽  
Carles Diez ◽  
Joel Salazar-Mendiguchía ◽  
Anna Fernandez-Falgueras ◽  
...  
Keyword(s):  
Rna Binding ◽  
Preventive Measures ◽  
Rare Variants ◽  
Early Recognition ◽  
Splicing Factor ◽  
Binding Motif ◽  
Familial Dilated Cardiomyopathy ◽  
Specific Alternative ◽  
Personalized Approach ◽  
Malignant Arrhythmias

The RBM20 gene encodes the muscle-specific splicing factor RNA-binding motif 20, a regulator of heart-specific alternative splicing. Nearly 40 potentially deleterious variants in RBM20 have been reported in the last ten years, being found to be associated with highly arrhythmogenic events in familial dilated cardiomyopathy. Frequently, malignant arrhythmias can be a primary manifestation of disease. The early recognition of arrhythmic genotypes is crucial in avoiding lethal episodes, as it may have an impact on the adoption of personalized preventive measures. Our study performs a comprehensive update of data concerning rare variants in RBM20 that are associated with malignant arrhythmogenic phenotypes with a focus on personalized medicine.

scholarly journals Effect of An 84-bp Deletion of the Receptor-Binding Domain on the ACE2 Binding Affinity of the SARS-CoV-2 Spike Protein: An In Silico Analysis

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 194
Author(s):  
Gábor Kemenesi ◽  
Gábor Endre Tóth ◽  
Dávid Bajusz ◽  
György M. Keserű ◽  
Gabriella Terhes ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Early Recognition ◽  
In Silico Analysis ◽  
Genetic Alterations ◽  
Binding Domain ◽  
Spike Protein ◽  
Evolutionary Strategy ◽  
Receptor Binding Domain ◽  
Base Pair Deletion ◽  
Therapeutic Research

SARS-CoV-2 is a recently emerged, novel human coronavirus responsible for the currently ongoing COVID-19 pandemic. Recombination is a well-known evolutionary strategy of coronaviruses, which may frequently result in significant genetic alterations, such as deletions throughout the genome. In this study we identified a co-infection with two genetically different SARS-CoV-2 viruses within a single patient sample via amplicon-based next generation sequencing in Hungary. The recessive strain contained an 84 base pair deletion in the receptor binding domain of the spike protein gene and was found to be gradually displaced by a dominant non-deleterious variant over-time. We have identified the region of the receptor-binding domain (RBD) that is affected by the mutation, created homology models of the RBDΔ84 mutant, and based on the available experimental data and calculations, we propose that the mutation has a deteriorating effect on the binding of RBD to the angiotensin-converting enzyme 2 (ACE2) receptor, which results in the negative selection of this variant. Extending the sequencing capacity toward the discovery of emerging recombinant or deleterious strains may facilitate the early recognition of novel strains with altered phenotypic attributes and understanding of key elements of spike protein evolution. Such studies may greatly contribute to future therapeutic research and general understanding of genomic processes of the virus.

scholarly journals LGG-28. NOVEL BRAF INTRAGENIC DELETION IN A GLIOMA: A CASE REPORT OF A PEDIATRIC PATIENT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii371-iii372
Author(s):  
Valerie Cruz Flores ◽  
Maxine Sutcliffe ◽  
Thomas Geller ◽  
Ignacio Gonzalez Gomez ◽  
Stephanie Smith ◽  
...  
Keyword(s):  
Pediatric Patient ◽  
Pilocytic Astrocytoma ◽  
Pediatric Population ◽  
Binding Pocket ◽  
Genetic Alterations ◽  
Low Grade ◽  
Braf Gene ◽  
Intragenic Deletion ◽  
Whole Genome Microarray ◽  
Intragenic Deletions

Abstract BACKGROUND Numerous variant BRAF genetic alterations have been associated with malignancies. BRAF activating fusions/mutations are frequently present in low grade gliomas. BRAF intragenic deletions have been reported in melanoma, but have not previously been reported in gliomas. OBJECTIVE To report a BRAF intragenic deletion in a pediatric patient with recurrent low-grade glioma. RESULTS A 3-year-old female underwent a complete resection of a posterior fossa pilocytic astrocytoma. She had recurrences at age 4, and then at age 9; pathology was consistent with pilocytic astrocytoma. Microarray analysis on sample from the first recurrence showed one region of loss encompassing 86 Kbp within the BRAF gene. The deletion breakpoints are within intron 1 and 9, resulting in loss of exons 2 through 9, inclusive. This has been previously described melanoma, but appears to be a novel finding in glioma. It is hypothesized that, since the loss retains the kinase and ATP binding pocket domains but deletes the N-terminal conserved region 1 and 2 (CR1, CR2) of the BRAF gene, it is likely functionally similar to the loss and activation resulting from the more usually described KIAA1549 and BRAF gene fusion. CONCLUSION This is the first BRAF intragenic deletion involving exons 2–9 reported in a glioma. Although 86kbp is small using whole genome microarray technology, it is large using sequencing strategies, and a targeted sequencing approach to investigate the BRAF gene would not readily identify this deletion. It is speculated that the deletion may be under ascertained in the pediatric population.

scholarly journals Expanding cancer predisposition genes with ultra-rare cancer-exclusive human variations

2020 ◽  
Author(s):  
Roni Rasnic ◽  
Nathan Linial ◽  
Michal Linial
Keyword(s):  
Genetic Predisposition ◽  
Rare Variants ◽  
Genetic Alterations ◽  
Cancer Predisposition ◽  
Rare Cancer ◽  
Uk Biobank ◽  
Independent Evidence ◽  
High Penetrance ◽  
Predisposition Genes ◽  
The Uk

AbstractIt is estimated that up to 10% of cancer incidents are attributed to inherited genetic alterations. Despite extensive research, there are still gaps in our understanding of genetic predisposition to cancer. It was theorized that ultra-rare variants partially account for the missing heritable component. We harness the UK BioBank dataset of ∼500,000 individuals, 14% of which were diagnosed with cancer, to detect ultra-rare, possibly high-penetrance cancer predisposition variants. We report on 115 cancer-exclusive ultra-rare variations (CUVs) and nominate 26 variants with additional independent evidence as cancer predisposition variants. We conclude that population cohorts are valuable source for expanding the collection of novel cancer predisposition genes.

scholarly journals Structural bioinformatics enhances mechanistic interpretation of genomic variation, demonstrated through the analyses of 935 distinct RAS family mutations

2020 ◽  
Author(s):  
Swarnendu Tripathi ◽  
Nikita R Dsouza ◽  
Raul Urrutia ◽  
Michael T Zimmermann
Keyword(s):  
Hot Spot ◽  
Adult Population ◽  
3D Structure ◽  
Genetic Alterations ◽  
Genomic Variation ◽  
Supplementary Information ◽  
High Yield ◽  
Clinical Genetics ◽  
Ras Genes ◽  
Ras Family

Abstract Motivation Protein-coding genetic alterations are frequently observed in Clinical Genetics, but the high yield of variants of uncertain significance remains a limitation in decision making. RAS-family GTPases are cancer drivers, but only 54 variants, across all family members, fall within well-known hotspots. However, extensive sequencing has identified 881 non-hotspot variants for which significance remains to be investigated. Results Here, we evaluate 935 missense variants from seven RAS genes, observed in cancer, RASopathies and the healthy adult population. We characterized hotspot variants, previously studied experimentally, using 63 sequence- and 3D structure-based scores, chosen by their breadth of biophysical properties. Applying scores that display best correlation with experimental measures, we report new valuable mechanistic inferences for both hot-spot and non-hotspot variants. Moreover, we demonstrate that 3D scores have little-to-no correlation with those based on DNA sequence, which are commonly used in Clinical Genetics. Thus, combined, these new knowledge bear significant relevance. Availability and implementation All genomic and 3D scores, and markdown for generating figures, are provided in our supplemental data. Contact [email protected] Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Neurotrophic Receptor Tyrosine Kinase 2 (NTRK2) Alterations in Low-Grade Gliomas: Report of a Novel Gene Fusion Partner in a Pilocytic Astrocytoma and Review of the Literature

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Siobhan S. Pattwell ◽  
Eric Q. Konnick ◽  
Yajuan J. Liu ◽  
Rebecca A. Yoda ◽  
Laligam N. Sekhar ◽  
...  
Keyword(s):  
Pilocytic Astrocytoma ◽  
Gene Fusion ◽  
Pediatric Population ◽  
Neurofibromatosis Type ◽  
Genetic Alterations ◽  
Neurotrophin Receptor ◽  
Low Grade ◽  
Fusion Partner ◽  
Tyrosine Kinase 2 ◽  
Cns Neoplasms

Pilocytic astrocytoma is a low-grade glial neoplasm of the central nervous system (CNS) that tends to occur in the pediatric population and less commonly presents in adults. Hereditary pilocytic astrocytoma is often associated with germline genetic alterations in the tumor suppressor NF1, the gene responsible for the syndrome neurofibromatosis type 1. Sporadic pilocytic astrocytoma frequently harbors somatic alterations in BRAF, with rare pilocytic astrocytomas containing alterations in FGFR1 and NTRK2. NTRK2 encodes for the protein tropomyosin receptor kinase B (TrkB), which is a neurotrophin receptor with high affinity for Brain-Derived Neurotrophic Factor (BDNF), and plays a role in several physiological functions of neurons, including cell survival and differentiation. In this report, we describe a novel PML-NTRK2 gene fusion occurring in an adult sporadic pilocytic astrocytoma and review the biology and implications of specific NTRK2 mutations occurring in CNS neoplasms.

scholarly journals The Role of Merlin/NF2 Loss in Meningioma Biology

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1633 ◽  
Author(s):  
Sungho Lee ◽  
Patrick J. Karas ◽  
Caroline C. Hadley ◽  
James C. Bayley V ◽  
A. Basit Khan ◽  
...  
Keyword(s):  
Early Recognition ◽  
Neurofibromatosis Type ◽  
Genetic Alterations ◽  
In Vivo Models ◽  
Inhibition Of Proliferation ◽  
Nf2 Gene ◽  
Sequencing Studies

Mutations in the neurofibromin 2 (NF2) gene were among the first genetic alterations implicated in meningioma tumorigenesis, based on analysis of neurofibromatosis type 2 (NF2) patients who not only develop vestibular schwannomas but later have a high incidence of meningiomas. The NF2 gene product, merlin, is a tumor suppressor that is thought to link the actin cytoskeleton with plasma membrane proteins and mediate contact-dependent inhibition of proliferation. However, the early recognition of the crucial role of NF2 mutations in the pathogenesis of the majority of meningiomas has not yet translated into useful clinical insights, due to the complexity of merlin’s many interacting partners and signaling pathways. Next-generation sequencing studies and increasingly sophisticated NF2-deletion-based in vitro and in vivo models have helped elucidate the consequences of merlin loss in meningioma pathogenesis. In this review, we seek to summarize recent findings and provide future directions toward potential therapeutics for this tumor.

Genetic Variants on SCN5A, KCNQ1, and KCNH2 in Patients with Ventricular Arrhythmias during Acute Myocardial Infarction in a Chinese Population

Cardiology ◽  
2019 ◽  
Vol 145 (1) ◽  
pp. 38-45 ◽  
Author(s):  
Feng Wang ◽  
Yang Liu ◽  
Hongtao Liao ◽  
Yumei Xue ◽  
Xianzhang Zhan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Association Study ◽  
Chinese Population ◽  
Ventricular Arrhythmias ◽  
Rare Variants ◽  
Allelic Frequency ◽  
Genotype Frequency ◽  
Missense Variants ◽  
Significant Difference

Objective: Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. About half of sudden deaths from AMI are mainly because of malignant ventricular arrhythmias (VA) after AMI. The sodium channel gene SCN5A and potassium channel genes KCNQ1 and KCNH2 have been widely reported to be genetic risk factors for arrhythmia including Brugada syndrome and long QT syndrome (LQTS). A few studies reported the association of SCN5A variant with ventricular tachycardia (VT)/ventricular fibrillation (VF) complicating AMI. However, little is known about the role of KCNQ1 and KCNH2 in AMI with VA (AMI_VA). This study focuses on investigating the potential variants on SCN5A, KCNQ1, and KCNH2 contributing to AMI with VA in a Chinese population. Materials and Methods: In total, 139 patients with AMI_VA, and 337 patients with AMI only, were included. Thirty exonic sites were selected to be screened. Sanger sequencing was used to detect variants. A subsequent association study was also performed between AMI_VA and AMI. Results: Twelve variants [5 on KCNH2(NM_000238.3), 3 on KCNQ1(NM_000218.2), and 4 on SCN5A(NM_198056.2)] were identified in AMI_VA patients. Only 5 (KCNH2: c.2690A>C; KCNQ1: c.1927G>A, c.1343delC; SCN5A: c.1673A>G, c.3578G>A) of them are missense variants. Two (KCNQ1: c.1343delC and SCN5A: c.3578G>A) of the missense variants were predicted to be clinically pathogenic. All these variants were further genotyped in an AMI without VA group. The association study identified a statistically significant difference in genotype frequency of KCNH2: c.1539C>T and KCNH2: c.1467C>T between the AMI and AMI_VA groups. Moreover, 2 rare variants (KCNQ1: c.1944C>T and SCN5A: c.3621C>T) showed an elevated allelic frequency (more than 1.5-fold) in the AMI_VA group when compared to the AMI group. Conclusion: Twelve variants (predicting from benign/VUS to pathogenic) were identified on KCNH2, KCNQ1, and SCN5A in patients with AMI_VA. Genotype frequency comparison between AMI_VA and AMI identified 2 significant common variants on KCNH2. Meanwhile, the allelic frequency of 2 rare variants on KCNQ1 and SCN5A, respectively, were identified to be enriched in AMI_VA, although there was no statistical significance. The present study suggests that the ion-channel genes KCNH2, KCNQ1, and SCN5A may contribute to the pathogenesis of VA during AMI.

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