Role of CACNA1C variants in Brugada syndrome: clinical aspects and genetic testing strategies

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
V Novelli ◽  
M Memmi ◽  
A Malovini ◽  
A Mazzanti ◽  
N Liu ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Brugada Syndrome ◽  
Genetic Variants ◽  
Clinical Aspects ◽  
Functional Evaluation ◽  
Discovery Cohort ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
The Impact

Abstract Background Inconsistent data support the role of CACNA1C as a disease-causing gene responsible for Brugada syndrome (BrS). As of today, the only gene consistently linked with BrS is SCN5A. Several CACNA1c genetic variants have been reported in association wirh BrS; however, due to the limited evidence, CACNA1C is not suggested for routine genetic screening for BrS. Purpose In this study, we carried out a systematic screening of CACNA1C gene, including a functional evaluation of the identified variants, in order to determine the yield of screening in a large series of BrS probands and to address the hypothesis that an appropriate clinical selection of patients would substantially improve the yield of genetic testing. Methods and results Overall 564 consecutive patients, referred for BrS genetic testing, were sequenced for CACNA1C gene. Patients were divided in two groups: discovery cohort (n=200 patients) and confirmation cohort (n=363 patients). Furthermore, analysis of the clinical phenotypes of a matched SCN5A positive BrS cohort (n=146) was included for phenotype characterization. In the discovery cohort we identified 11 different genetic variants of whom 2 (18%) were considered as potentially causative based on ACMG guidelines. However, a large proportion (81%) was classified as variants of unknown significance (VUS). Functional evaluation of the identified variants, including pathogenic and VUS, was assessed by patch-clamp and immunofluorescence studies. Re-evaluation of the variants, including functional studies results, indicated an increase of pathogenic or likely pathogenic variants (81%) getting a yield of screening of 5% in the discovery cohort. Results from the confirmation cohort confirmed a low rate of CACNA1C carriers with a yield of screening of 2.2%. Analysing the clinical phenotype of all CACNA1C carriers showed a significantly shorter QTc [371 ms ± 16 ms vs. 399±18 ms; p=0.000004]. Furthermore, the prevalence of CACNA1C variants was highest (12.9%) among patients with a QTc in the lowest quartile (QTc <390 ms). ROC curve showed an AUC of 0.91 for QTc a cut-off of 385 ms, suggesting a high predictive accuracy. Conclusion We confirmed that CACNA1C variants are not a common cause of BrS, with a yield of screening of 2–5%. However, pathogenic variants are more frequent (12.5%) in patients with a shorter QTc, suggesting a genetic testing strategy in this subgroup of BrS patients. Furthermore, our data highlights the impact of robust functional studies to improve variant classification and reduce uncertainties. Funding Acknowledgement Type of funding source: None

Genetic variants involved in bromodomain-containing protein 4 (BRD4) regulating pathway to predict outcomes in patients with metastatic colorectal cancer: Results from FIRE3 and MAVERICC trials.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 232-232
Author(s):  
Jingyuan Wang ◽  
Yi Xiao ◽  
Fotios Loupakis ◽  
Sebastian Stintzing ◽  
Hiroyuki Arai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Genetic Variants ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Discovery Cohort ◽  
Strong Trend ◽  
The Impact ◽  
First Time ◽  
Worse Prognosis

232 Background: BRD4 plays an important role in transcription, DNA repair and drug resistance. High expression and polymorphisms of BRD4 regulating pathways were reported to be related to worse prognosis in colorectal cancer. Therefore, we hypothesized that genetic variants in BRD4 regulating pathway may predict first-line treatment outcome in mCRC pts. Methods: The impact on outcome of 22 SNPs in 7 genes involved in BRD4 regulating pathway (BRD4, SIPA1, MYC, 53BP1, H2AX, BATF, CD47) was analyzed through the OncoArray, a customized array manufactured by Illumina, on genomic DNA from blood samples of pts enrolled in 2 randomized trials. MAVERICC FOLFIRI/bevacizumab (bev) arm served as discovery cohort (N = 107), FIRE3 FOLFIRI/bev arm as validation (N = 107) and FOLFIRI/cetuximab (cet) arm as control (N = 129). Results: In the discovery cohort, right(R)-sided pts with BRD4 rs4808272 any G allele (N = 46) showed significantly shorter PFS (9.5 vs 18 m) compared to carriers of A/A (N = 21) in both uni- and multi-variable analysis ( p < .01); R-sided pts carrying any T allele of BATF rs7161377 (N = 50) showed longer PFS (12.3 vs 6.8 m) compared to carriers of C/C (N = 14) in univariate analysis ( p < .05) and had a strong trend in multivariable analysis ( p = .06). These findings were all validated in R-sided pts in FIRE3 bev arm (BRD4 rs4808272, PFS 9.8 vs 18.7 m; BATF rs7161377, PFS 15.1 vs 4.2 m) in uni- (both p < .01) and multi-variable ( p = .08 and p < .05 respectively) analysis. No significant association was observed in the control arm. Interestingly, pts carrying CD47 rs3206652 any C allele (N = 13) only showed significant longer PFS (9.0 vs 3.0 m, univariable p < .01 and multivariable p = .07) in the R-sided pts of FIRE3 cet cohort, but no association was observed in the bev-based treatment. Conclusions: Our study demonstrates for the first time that BRD4 and BATF polymorphisms may predict outcomes of bev-based treatment in R-sided mCRC pts; Meanwhile CD47 polymorphism could predict outcomes of cet-based treatment in R-sided mCRC pts. This finding supports a possible role of BRD4 regulating pathway in contributing to resistance to anti-VEGF/EGFR treatment.

The role of CACNA1C in Brugada syndrome: prevalence and phenotype of probands referred for genetic testing

Heart Rhythm ◽  
2022 ◽  
Author(s):  
Valeria Novelli ◽  
Mirella Memmi ◽  
Alberto Malovini ◽  
Andrea Mazzanti ◽  
Nian Liu ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Brugada Syndrome

scholarly journals Personalized Nutrition for Management of Micronutrient Deficiency—Literature Review in Non-bariatric Populations and Possible Utility in Bariatric Cohort

2020 ◽  
Vol 30 (9) ◽  
pp. 3570-3582
Author(s):  
Shannon Galyean ◽  
Dhanashree Sawant ◽  
Andrew C. Shin
Keyword(s):  
Bariatric Surgery ◽  
Morbid Obesity ◽  
Genetic Testing ◽  
High Risk ◽  
Genetic Variants ◽  
Micronutrient Deficiency ◽  
High Dose ◽  
Micronutrient Deficiencies ◽  
Personalized Nutrition

Abstract Background Bariatric surgery can effectively treat morbid obesity; however, micronutrient deficiencies are common despite recommendations for high-dose supplements. Genetic predisposition to deficiencies underscores necessary identification of high-risk candidates. Personalized nutrition (PN) can be a tool to manage these deficiencies. Methods Medline, PubMed, and Google Scholar were searched. Articles involving genetic testing, micronutrient metabolism, and bariatric surgery were included. Results Studies show associations between genetic variants and micronutrient metabolism. Research demonstrates genetic testing to be a predictor for outcomes among obesity and bariatric surgery populations. There is limited research in bariatric surgery and micronutrient genetic variants. Conclusion Genotype-based PN is becoming feasible to provide an effective treatment of micronutrient deficiencies associated with bariatric surgery. The role of genomic technology in micronutrient recommendations needs further investigation.

scholarly journals Exome sequencing identifies novel AD-associated genes.

2020 ◽  
Author(s):  
Henne Holstege ◽  
Marc Hulsman ◽  
Camille Charbonnier ◽  
Benjamin Grenier-Boley ◽  
Olivier Quenez ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Genetic Variants ◽  
Rare Variants ◽  
Mendelian Inheritance ◽  
Loss Of Function ◽  
App Processing ◽  
Complex Disorders ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
The Impact

Background: With the development of next-generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimers Disease (AD), reaching odds ratios comparable with the APOE-ε4 allele, the main common AD genetic risk factor. Here, we set out to identify additional AD-associated genes by an exome-wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls. Method: We integrated the data from 25,982 samples from the European ADES consortium and the American ADSP consortium. We developed new techniques to homogenise and analyse these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of dementia were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analysed using a burden analysis, including both non-synonymous and loss-of-function rare variants, the impact of which was prioritised using REVEL. Result: We confirmed that carrying rare protein-damaging genetic variants in TREM2, SORL1 or ABCA7 is associated with increased AD-risk. Moreover, we found that carrying rare damaging variants in the microglial ATP8B4 gene was significantly associated with AD, and we found suggestive evidence that rare variants in ADAM10, ABCA1, ORC6, B3GNT4 and SRC genes associated with increased AD risk. High-impact variants in these genes were mostly extremely rare and enriched in AD patients with earlier ages at onset. Additionally, we identified two suggestive protective associations in CBX3 and PRSS3. We are currently replicating these associations in independent datasets. Conclusion: With our newly developed homogenisation methods, we identified novel genetic determinants of AD which provide further evidence for a pivotal role of APP processing, lipid metabolism, and microglia and neuro-inflammatory processes in AD pathophysiology.

scholarly journals The Spectrum of Genetic Variants Associated with the Development of Monogenic Obesity in Qatar

Obesity Facts ◽  
2022 ◽  
Author(s):  
Nadien AbouHashem ◽  
Roan E. Zaied ◽  
Kholoud Al-Shafai ◽  
Mariam Nofal ◽  
Najeeb Syed ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Rare Variants ◽  
Normal Weight ◽  
Routine Testing ◽  
Monogenic Obesity ◽  
Syndromic Obesity ◽  
The Impact

Introduction: Monogenic obesity (MO) is a rare genetic disease characterized by severe early-onset obesity in affected individuals. Previous genetic studies revealed 8 definitive genes for monogenic non-syndromic obesity; many were discovered in consanguineous populations. Here, we examined MO in the Qatari population, whose population is largely consanguineous (54%) and characterized by extensive obesity (45%). Methods: Whole genome sequences of Qatar Biobank samples from 250 subjects with obesity and 250 subjects with normal weight, obtained in association with the Qatar Genome Programme, were searched for genetic variants in the genes known to be associated with MO (i.e., LEP, LEPR, POMC, PCSK1, MC3R, MC4R, MRAP2 and ADCY3). The impact of the variants identified was investigated utilizing in silico tools for prediction in combination with protein visualization by PyMOL. Results: We identified potential MO variants in more than 5% of the cases in our cohort. We revealed 11 rare variants in 6 of the genes targeted, including two disease-causing variants in MC4R and MRAP2, all of which were heterozygous. Moreover, enrichment of a heterozygous ADCY3 variant (c.1658C>T; p.A553V) appeared to cause severe obesity in an autosomal dominant manner. Conclusion: These findings highlight the importance of implementing routine testing for genetic variants that predispose for MO in Qatar. Clearly, additional studies of this nature on populations not yet examined are required. At the same time, functional investigations, both in vitro and in vivo, are necessary in order to better understand the role of the variants identified in the pathogenesis of obesity.

scholarly journals Advances and challenges in cancer treatment and nutraceutical prevention: the possible role of dietary phenols in BRCA regulation

2021 ◽  
Author(s):  
Haroon Khan ◽  
Fabiana Labanca ◽  
Hammad Ullah ◽  
Yaseen Hussain ◽  
Nikolay T. Tzvetkov ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Natural Products ◽  
Cancer Treatment ◽  
Clinical Aspects ◽  
Anti Cancer ◽  
Brca 1 ◽  
Brca 2 ◽  
The Impact ◽  
Cancer Activity

AbstractOver the years, the attention towards the role of phytochemicals in dietary natural products in reducing the risk of developing cancer is rising. Cancer is the second primary cause of mortality worldwide. The current therapeutic options for cancer treatment are surgical excision, immunotherapy, chemotherapy, and radiotherapy. Unfortunately, in case of metastases or chemoresistance, the treatment options become very limited. Despite the advances in medical and pharmaceutical sciences, the impact of available treatments on survival is not satisfactory. Recently, natural products are a great deal of interest as potential anti-cancer agents. Among them, phenolic compounds have gained a great deal of interest, thanks to their anti-cancer activity. The present review focuses on the suppression of cancer by targeting BRCA gene expression using dietary polyphenols, as well as the clinical aspects of polyphenolic agents in cancer therapy. They regulate specific key processes involved in cancer progression and modulate the expression of oncogenic proteins, like p27, p21, and p53, which may lead to apoptosis, cell cycle arrest, inhibition of cell proliferation, and, consequently, cancer suppression. Thus, one of the mechanisms underlying the anti-cancer activity of phenolics involves the regulation of tumor suppressor genes. Among them, the BRCA genes, with the two forms (BRCA-1 and BRCA-2), play a pivotal role in cancer protection and prevention. BRCA germline mutations are associated with an increased risk of developing several types of cancers, including ovarian, breast, and prostate cancers. BRCA genes also play a key role in the sensitivity and response of cancer cells to specific pharmacological treatments. As the importance of BRCA-1 and BRCA-2 in reducing cancer invasiveness, repairing DNA damages, oncosoppression, and cell cycle checkpoint, their regulation by natural molecules has been examined.

Expanding the Boundaries of Combined Renal Replacement Therapy for Non-Renal Indications

2018 ◽  
Vol 47 (1-3) ◽  
pp. 69-72 ◽  
Author(s):  
Mayanka Kamboj ◽  
Amir Kazory
Keyword(s):  
Hepatic Encephalopathy ◽  
Renal Replacement Therapy ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Replacement Therapy ◽  
Ammonia Level ◽  
Clinical Aspects ◽  
Optimal Timing ◽  
The Impact

Over the last decades, there have been major advancements in the field of renal replacement therapy (RRT) with utilization of newer technologies and advent of various modalities. Once exclusively used for treatment of renal failure and its metabolic consequences, the science of RRT has expanded to include non-renal indications such as treatment of fluid overload in patients with refractory heart failure. Hepatic encephalopathy due to sudden rise in serum ammonia level in the setting of acute liver failure represents an underexplored area in which RRT can potentially be helpful. While the key role of hyperammonemia in the pathogenesis of hepatic encephalopathy in patients with liver failure is well established, emerging data points to distinct pathophysiologic mechanisms underlying chronic alterations in neural metabolic functions and acute changes in cerebral perfusion. In the acute setting, ammonia can cross the blood–brain barrier at high levels leading to sudden formation of strong osmolytes, significant transcellular shift of water, and cerebral edema. Herein, we provide a brief overview of the role of RRT in management of acute hyperammonemia in the setting of acute liver failure and discuss the practical aspects of the available therapeutic modalities. Larger studies are needed to shed light on a number of clinical aspects such as the impact on the outcomes, criteria for selection of the patients that would benefit most from this therapeutic approach, optimal timing of initiation of RRT, and the most appropriate modality.

scholarly journals Functional validation of genetic variants identified by next generation sequencing in malformations of cortical development

2021 ◽  
Author(s):  
Dalila De Vita
Keyword(s):  
Next Generation Sequencing ◽  
Genetic Variants ◽  
Cortical Development ◽  
Next Generation ◽  
Malformations Of Cortical Development ◽  
Functional Studies ◽  
Generation Sequencing ◽  
In Vitro Treatment

Malformations of cortical development (MCDs) result from a disruption in the process of the human brain cortex formation: currently, there are no pharmacological treatments for diffuse MCDs. Next-generation sequencing has accelerated the identification of MCDs causing genes: in some cases, functional studies are needed to clarify the role of genetic variants. The aim of this PhD project has been to apply a multidisciplinary approach to identify causative mutations in patients with MCDs, validate the pathogenic role of the identified mutations, and assess the effectiveness of novel in vitro treatment for mTOR pathway related MCDs.

scholarly journals Role of SCN5A coding and non-coding sequences in Brugada syndrome onset: What’s behind the scenes?

2017 ◽  
Author(s):  
Houria Daimi ◽  
Amel Haj Khelil ◽  
Ali Neji ◽  
Khaldoun Ben Hamda ◽  
Sabri Maaoui ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Binding Site ◽  
Candidate Genes ◽  
Brugada Syndrome ◽  
Genetic Variants ◽  
Sequence Variant ◽  
Α Subunit ◽  
Coding Sequence ◽  
Cardiac Sodium Channel ◽  
Scn5a Gene

AbstractBrugada syndrome (BrS) is a rare inherited cardiac arrhythmia associated with a high risk of sudden cardiac death (SCD) due to ventricular fibrillation (VF). BrS is characterized by coved-type ST-segment elevation in the right precordial leads (V1-V3) in the absence of structural heart disease. This pattern is spontaneous, or is unmasked by intravenous administration of Class I antiarrhythmic drugs. The SCN5A-encoded α-subunit of the NaV1.5 cardiac sodium channel has been linked to BrS, and mutations in SCN5A are identified in 15–30% of BrS cases. Genetic testing of BrS patients generally involves sequencing of protein-coding portions and flanking intronic regions of SCN5A, according to recent international guidelines. This excludes the regulatory untranslated regions (5’UTR and 3’UTR) from the routine genetic testing of BrS patients. We here screened the coding sequence, the flanking intronic regions as well as the 5’ and 3’UTR regions of SCN5A gene and further five candidate genes (GPD1L, SCN1B, KCNE3, SCN4B, and MOG1) in a Tunisian family diagnosed with Brugada syndrome.A new Q1000K mutation was identified on the SCN5A gene along with two common polymorphisms (H558R and D1819). Furthermore, multiple genetic variants were identified on the SCN5A 3’UTR, one of which is predicted to create additional microRNA (miRNAs) binding site for miR-1270. Additionally, we identified the hsa-miR-219a rs107822. No relevant coding sequence variant was identified in the remaining studied candidate genes. Although Q1000K is localized in the conserved binding site of MOG1 which predicts a functional consequence, this new mutation along with the additional variants were differentially distributed among the family members without any clear genotype-phenotype concordance. This gives extra evidences about the complexity of the disease and suggests that the occurrence and prognosis of BrS is most likely controlled by a combination of multiple genetic factors and exposures, rather than a single polymorphism/mutation. Most SCN5A polymorphisms were localized in non-coding regions hypothesizing an impact on the miRNA-target complementarities. In this regard, over-expression of miR-1270 led to a significant decrease of luciferase activity suggesting a direct role regulating SCN5A. Therefore, genetic variants that disrupt its binding affinity to SCN5A 3’UTR and/or its expression might cause loss of normal repression control and be associated to BrS.

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.

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