scholarly journals Update on Genetic Basis of Brugada Syndrome: Monogenic, Polygenic or Oligogenic?

2020 ◽  
Vol 21 (19) ◽  
pp. 7155 ◽  
Author(s):  
Oscar Campuzano ◽  
Georgia Sarquella-Brugada ◽  
Sergi Cesar ◽  
Elena Arbelo ◽  
Josep Brugada ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Genetic Basis ◽  
Rare Variants ◽  
Genetic Diagnosis ◽  
Genetic Alterations ◽  
Pathogenic Variants ◽  
Oligogenic Inheritance ◽  
The Many ◽  
Scn5a Gene

Brugada syndrome is a rare inherited arrhythmogenic disease leading to ventricular fibrillation and high risk of sudden death. In 1998, this syndrome was linked with a genetic variant with an autosomal dominant pattern of inheritance. To date, rare variants identified in more than 40 genes have been potentially associated with this disease. Variants in regulatory regions, combinations of common variants and other genetic alterations are also proposed as potential origins of Brugada syndrome, suggesting a polygenic or oligogenic inheritance pattern. However, most of these genetic alterations remain of questionable causality; indeed, rare pathogenic variants in the SCN5A gene are the only established cause of Brugada syndrome. Comprehensive analysis of all reported genetic alterations identified the origin of disease in no more than 40% of diagnosed cases. Therefore, identifying the cause of this rare arrhythmogenic disease in the many families without a genetic diagnosis is a major current challenge in Brugada syndrome. Additional challenges are interpretation/classification of variants and translation of genetic data into clinical practice. Further studies focused on unraveling the pathophysiological mechanisms underlying the disease are needed. Here we provide an update on the genetic basis of Brugada syndrome.

scholarly journals Mutational Spectrum Analysis of Seven Genes Associated with Thyroid Dyshormonogenesis

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Xi Chen ◽  
Xiaohong Kong ◽  
Jie Zhu ◽  
Tingting Zhang ◽  
Yanwei Li ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Genetic Alterations ◽  
Chinese Patients ◽  
Study Cohort ◽  
Chinese Han ◽  
Hormone Synthesis ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Thyroid Dyshormonogenesis ◽  
Generation Sequencing

Objective. Thyroid dyshormonogenesis (DH) is a genetically heterogeneous inherited disorder caused by thyroid hormone synthesis abnormalities. This study aims at comprehensively characterizing the mutation spectrum in Chinese patients with DH. Subjects and Methods. We utilized next-generation sequencing to screen for mutations in seven DH-associated genes (TPO, DUOX2, TG, DUOXA2, SLC26A4, SLC5A5, and IYD) in 21 Chinese Han patients with DH from Xinjiang Province. Results. Twenty-eight rare nonpolymorphic variants were found in 19 patients (90.5%), including 19, 5, 3, and 1 variants in DUOX2, TG, DUOXA2, and SLC26A4, respectively. Thirteen (62%) patients carried monogenic mutations, and six (28.5%) carried oligogenic mutations. Fifteen (71%) patients carried 2 or more DUOX2 (14) or DUOXA2 (1) variants. The genetic basis of DH in nine (43%) patients harboring biallelic or triallelic pathogenic variants was resolved. Seventeen patients (81%) carried DUOX2 mutations, most commonly p.R1110Q or p.K530X. No correlations were found between DUOX2 mutation types or numbers and clinical phenotypes. Conclusions. DUOX2 mutations were the most predominant genetic alterations of DH in the study cohort. Oligogenicity may explain the genetic basis of disease in many DH patients. Functional studies and further clinical studies with larger DH patient cohorts are needed to validate the roles of the mutations identified in this study.

scholarly journals Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Zeinab Fadaie ◽  
Laura Whelan ◽  
Tamar Ben-Yosef ◽  
Adrian Dockery ◽  
Zelia Corradi ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Variants ◽  
Genetic Diagnosis ◽  
Whole Genome ◽  
Retinal Diseases ◽  
Structural Variants ◽  
Pathogenic Variants ◽  
Coding Variants

AbstractInherited retinal diseases (IRDs) are a major cause of visual impairment. These clinically heterogeneous disorders are caused by pathogenic variants in more than 270 genes. As 30–40% of cases remain genetically unexplained following conventional genetic testing, we aimed to obtain a genetic diagnosis in an IRD cohort in which the genetic cause was not found using whole-exome sequencing or targeted capture sequencing. We performed whole-genome sequencing (WGS) to identify causative variants in 100 unresolved cases. After initial prioritization, we performed an in-depth interrogation of all noncoding and structural variants in genes when one candidate variant was detected. In addition, functional analysis of putative splice-altering variants was performed using in vitro splice assays. We identified the genetic cause of the disease in 24 patients. Causative coding variants were observed in genes such as ATXN7, CEP78, EYS, FAM161A, and HGSNAT. Gene disrupting structural variants were also detected in ATXN7, PRPF31, and RPGRIP1. In 14 monoallelic cases, we prioritized candidate noncanonical splice sites or deep-intronic variants that were predicted to disrupt the splicing process based on in silico analyses. Of these, seven cases were resolved as they carried pathogenic splice defects. WGS is a powerful tool to identify causative variants residing outside coding regions or heterozygous structural variants. This approach was most efficient in cases with a distinct clinical diagnosis. In addition, in vitro splice assays provide important evidence of the pathogenicity of rare variants.

Mutation Load of Multiple Ion Channel Gene Mutations in Brugada Syndrome

Cardiology ◽  
2017 ◽  
Vol 137 (4) ◽  
pp. 256-260 ◽  
Author(s):  
Francesca Gualandi ◽  
Fatima Zaraket ◽  
Michele Malagù ◽  
Giulia Parmeggiani ◽  
Cecilia Trabanelli ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Genetic Diagnosis ◽  
Gene Mutations ◽  
Mutation Load ◽  
Pathogenic Variants ◽  
Digenic Inheritance ◽  
Double Heterozygosity ◽  
Death Cases ◽  
Generation Sequencing

Brugada syndrome is a primary arrhythmic syndrome that accounts for 20% of all sudden cardiac death cases in individuals with a structurally normal heart. Pathogenic variants associated with Brugada syndrome have been identified in over 19 genes, with SCN5A as a pivotal gene accounting for nearly 30% of cases. In contrast to other arrhythmogenic channelopathies (such as long QT syndrome), digenic inheritance has never been reported in Brugada syndrome. Exploring 66 cardiac genes using a new custom next-generation sequencing panel, we identified a double heterozygosity for pathogenic mutations in SCN5A and TRPM4 in a Brugada syndrome patient. The parents were heterozygous for each variation. This novel finding highlights the role of mutation load in Brugada syndrome and strongly suggests the adoption of a gene panel to obtain an accurate genetic diagnosis, which is mandatory for risk stratification, prevention, and therapy.

Screening of BRCA1/2 deep intronic regions by targeted gene sequencing identifies the first germline BRCA1 variant causing pseudoexon activation in a patient with breast/ovarian cancer

2018 ◽  
Vol 56 (2) ◽  
pp. 63-74 ◽  
Author(s):  
Gemma Montalban ◽  
Sandra Bonache ◽  
Alejandro Moles-Fernández ◽  
Alexandra Gisbert-Beamud ◽  
Anna Tenés ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Rare Variants ◽  
Genetic Diagnosis ◽  
Gene Sequencing ◽  
Functional Protein ◽  
Coding Regions ◽  
Aberrant Transcript ◽  
Pathogenic Variants ◽  
Novel Transcript ◽  
Targeted Gene Sequencing

BackgroundGenetic analysis of BRCA1 and BRCA2 for the diagnosis of hereditary breast and ovarian cancer (HBOC) is commonly restricted to coding regions and exon-intron boundaries. Although germline pathogenic variants in these regions explain about ~20% of HBOC cases, there is still an important fraction that remains undiagnosed. We have screened BRCA1/2 deep intronic regions to identify potential spliceogenic variants that could explain part of the missing HBOC susceptibility.MethodsWe analysed BRCA1/2 deep intronic regions by targeted gene sequencing in 192 high-risk HBOC families testing negative for BRCA1/2 during conventional analysis. Rare variants (MAF <0.005) predicted to create/activate splice sites were selected for further characterisation in patient RNA. The splicing outcome was analysed by RT-PCR and Sanger sequencing, and allelic imbalance was also determined when heterozygous exonic loci were present.ResultsA novel transcript was detected in BRCA1 c.4185+4105C>T variant carrier. This variant promotes the inclusion of a pseudoexon in mature mRNA, generating an aberrant transcript predicted to encode for a non-functional protein. Quantitative and allele-specific assays determined haploinsufficiency in the variant carrier, supporting a pathogenic effect for this variant. Genotyping of 1030 HBOC cases and 327 controls did not identify additional carriers in Spanish population.ConclusionScreening of BRCA1/2 intronic regions has identified the first BRCA1 deep intronic variant associated with HBOC by pseudoexon activation. Although the frequency of deleterious variants in these regions appears to be low, our study highlights the importance of studying non-coding regions and performing comprehensive RNA assays to complement genetic diagnosis.

scholarly journals ISSAID/EMQN Best Practice Guidelines for the Genetic Diagnosis of Monogenic Autoinflammatory Diseases in the Next-Generation Sequencing Era

2020 ◽  
Vol 66 (4) ◽  
pp. 525-536 ◽  
Author(s):  
Yael Shinar ◽  
Isabella Ceccherini ◽  
Dorota Rowczenio ◽  
Ivona Aksentijevich ◽  
Juan Arostegui ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Best Practice ◽  
Copy Number Variants ◽  
Genetic Diagnosis ◽  
Genetic Alterations ◽  
Autoinflammatory Diseases ◽  
Next Generation ◽  
Disease Category ◽  
Pathogenic Variants ◽  
Generation Sequencing

Abstract Background Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential. Methods The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting. Results In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease. Conclusions These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients.

Monogenic and oligogenic cardiovascular diseases: genetics of arrhythmias—Brugada syndrome

ESC CardioMed ◽  
2018 ◽  
pp. 679-682
Author(s):  
Sonia Van Dooren ◽  
Dorien Daneels ◽  
Gudrun Pappaert ◽  
Maryse Bonduelle ◽  
Pedro Brugada
Keyword(s):  
Sodium Channel ◽  
Brugada Syndrome ◽  
Rare Variants ◽  
Diagnostic Yield ◽  
Molecular Genetic ◽  
Susceptibility Gene ◽  
Incomplete Penetrance ◽  
Gene Encoding ◽  
Pathogenic Variants ◽  
Complex Inheritance

The heritable arrhythmogenic disorder Brugada syndrome (BrS), a cardiac ion channelopathy first described in 1992, is inherited as an autosomal dominant trait characterized by incomplete penetrance, variable expression, and phenotypic overlap. These characteristics all complicate the elucidation of the underlying molecular genetic pathway. Clearly, SCN5A, the gene encoding the pore-forming alpha subunit of the cardiac sodium channel, is the major susceptibility gene associated with BrS: 20–30% of BrS patients harbour pathogenic variants in this gene and BrS patients have a more than eight times higher burden of rare variants in this gene compared to controls. Rare pathogenic variants have also been reported in several sodium, potassium, and calcium channel genes, pacemaker genes, and sodium channel interacting genes. Given the minor collective contribution of these additional BrS-associated genes to the total genetic diagnostic yield, the hypothesis has been raised that other (genetic) determinants are involved. Indeed, the monogenic nature of BrS has been questioned and more support has recently been gained for the hypothesis of a complex inheritance based on genome-wide and gene panel studies. Probably, the BrS inheritance pattern is a continuum ranging from a monogenic, over an oligogenic towards even a polygenic spectrum. This, however, further impedes the interpretation of the contribution of (likely) pathogenic variants to the phenotype and urges for a cautious policy in a prenatal and preimplantation genetic diagnostic context: in many cases disease prevention will imply a risk reduction instead of an elimination of disease (development).

299 The prevalence and role of SCN10A variants in Han Chinese patients with Brugada syndrome: the SADS-TW BrS registry

2020 ◽  
Vol 41 (Supplement_1) ◽  
Author(s):  
C-Y Chen ◽  
Y-B Liu ◽  
T-P Lu ◽  
Q-Y Yu ◽  
L-Y Lin ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Rare Variants ◽  
Han Chinese ◽  
Chinese Patients ◽  
P Value ◽  
Common Variants ◽  
Pathogenic Variants ◽  
In Silico Analyses ◽  
Generation Sequencing

Abstract On Behalf SADS-TW BrS registry Background Brugada syndrome (BrS) is an inheritable arrhythmic disease responsible for sudden cardiac death. Information on the prevalence and role of SCN10A variants in BrS is limited and equivocal. Purpose We aimed to investigate the prevalence and role of SCN10A variants in BrS in Han Chinese. Methods From 2000 to 2017, we prospectively and consecutively enrolled 176 unrelated BrS patients from the Han Chinese population in Taiwan (the SADS-TW BrS registry). Thirty-four BrS-related genes were screened by next-generation sequencing, using Taiwan Biobank as the population reference. The pathogenicity was evaluated by literature review and in silico analyses, including the SKAT-O algorithm. Results The SKAT-O algorithm showed that rare variants of SCN10A, but not common variants, were significantly different between BrS patients and healthy controls in the additive and dominant models (p-value &lt;0.001), suggesting that rare SCN10A variants may play a role in BrS. Six likely pathogenic SCN10A variants were found in 6 patients and were compared to 25 pathogenic or likely pathogenic SCN5A variants found in 29 patients. The patients with likely pathogenic SCN10A variants tended to exhibit sudden death in older age and have a shorter QRS interval than those carrying pathogenic or likely pathogenic SCN5A variants or no variants in either gene (p = 0.06, 0.07, respectively). Collectively, the prevalence of likely pathogenic SCN10A variants was 3.4% in Han Chinese patients with BrS in Taiwan. Conclusions SCN10A likely pathogenic variants were present in 3.4% of Han Chinese BrS patients. Rare SCN10A variants may play a role in BrS, and may have impact on clinical and electrocardiographic manifestations. Table 1. Patient Nucleotide Amino acid TWB gnomAD_EA REVEL CADD PHRED SIFT Polyphen-2 GERP++ 1 c.5789A &gt; T p.D1930V 0.001318 0.0008700 0.479 24.5 Damaging Possibly damaging 4.22 2 c.2341G &gt; A p.G781R 0 0.00005301 0.866 33 Damaging Probably damaging 4.83 3 c.5587C &gt; T p.R1863W 0.000502 0 0.832 27.8 Damaging Probably damaging 1.97 4 c.2161C &gt; T p.P721S 0.000989 0.0009016 0.933 28.5 Damaging Probably damaging 4.19 5 c.3749G &gt; A p.R1250Q 0 0 0.907 31 Damaging Probably damaging 4.23 6 c.1825A &gt; T p.R609W 0.000659 0.0001591 0.811 32 Damaging Probably damaging 4.28 Clinical and predicted functional characteristics of 6 likely pathogenic SCN10A variants. EA = East Asian; GERP = Genomic Evolutionary Rate Profiling; TWB = Taiwan Biobank. Transcript: NM_006514.3. Abstract 299 Figure. Location of the SCN10A variants

Effectiveness of Supervised Classification Models for Hate Speech on Twitter

2020 ◽  
Author(s):  
Kunal Srivastava ◽  
Ryan Tabrizi ◽  
Ayaan Rahim ◽  
Lauryn Nakamitsu
Keyword(s):  
Supervised Classification ◽  
Hate Speech ◽  
The Internet ◽  
Classification Models ◽  
Personal Attack ◽  
Political Beliefs ◽  
The Many ◽  
Primary Medium ◽  
Offensive Speech

<div> <div> <div> <p>Abstract </p> <p>The ceaseless connectivity imposed by the internet has made many vulnerable to offensive comments, be it their physical appearance, political beliefs, or religion. Some define hate speech as any kind of personal attack on one’s identity or beliefs. Of the many sites that grant the ability to spread such offensive speech, Twitter has arguably become the primary medium for individuals and groups to spread these hurtful comments. Such comments typically fail to be detected by Twitter’s anti-hate system and can linger online for hours before finally being taken down. Through sentiment analysis, this algorithm is able to distinguish hate speech effectively through the classification of sentiment. </p> </div> </div> </div>

Future Directions

2020 ◽  
pp. 476-479
Author(s):  
Marc N. Potenza ◽  
Kyle A. Faust ◽  
David Faust
Keyword(s):  
Technology Development ◽  
Digital Technologies ◽  
World Health ◽  
International Classification Of Disease ◽  
Levels Of Use ◽  
Pornography Use ◽  
Negative Impacts ◽  
Mental Health Treatments ◽  
The Many

As digital technology development continues to expand, both its positive and negative applications have also grown. As such, it is essential to continue gathering data on the many types of digital technologies, their overall effects, and their impact on public health. The World Health Organization’s inclusion of Gaming Disorder in the eleventh edition of the International Classification of Disease (ICD-11) indicates that some of the problematic effects of gaming are similar to those of substance-use disorders and gambling. Certain behaviors easily engaged in via the internet may also lead to compulsive levels of use in certain users, such as shopping or pornography use. In contrast, digital technologies can also lead to improvements in and wider accessibility to mental health treatments. Furthermore, various types of digital technologies can also lead to benefits such as increased productivity or social functioning. By more effectively understanding the impacts of all types of digital technologies, we can aim to maximize their benefits while minimizing or preventing their negative impacts.

Sign in / Sign up

Export Citation Format

Share Document