scholarly journals A Customized NGS-Based Resequencing Gene Panel to Identify Genetic Variants in Dementing Disorders: Preliminary Results

2019 ◽  
Author(s):  
Giuseppe Lanza ◽  
Francesco Calì ◽  
Mirella Vinci ◽  
Filomena Irene Ilaria Cosentino ◽  
Mariangela Tripodi ◽  
...  
Keyword(s):  
Genetic Variants ◽  
In Silico ◽  
Ad Hoc ◽  
In Silico Analysis ◽  
Gene Panel ◽  
Future Application ◽  
Rare Genetic Variants ◽  
Reduced Costs ◽  
Next Generation Sequencing Ngs ◽  
Dementing Disorders

Background: Advancements in the next-generation sequencing (NGS) techniques have allowed for efficient genetic variant detection at reduced costs. Methods: We describe an ad hoc NGS-based custom designed resequencing gene panel to identify genetic variants in 8 patients with dementing disorders. Results: We found variants of TREM2 and APP genes in three patients; these have been previously identified as pathogenic or likely pathogenic and, therefore, considered as “Disease Causing”. In the remaining subjects, the pathogenicity was evaluated on the in silico analysis, according to the guidelines of the American College of Medical Genetics. In one patient, the p.R205W variant was causative of the disease, thus considered as “Possibly Disease Causing”. The variants found from the other four subjects in the CSF1R, SERPINI1, GRN, and APP genes revealed discordant in silico results and, therefore, it was not possible to assign a definitive pathogenicity. Conclusions: Notwithstanding the limitations of a customized panel, we detected some rare genetic variants with a probable disease association. The future application of NGS techniques and the further replication of these experimental data will replace the so-called “gene by gene” approach with a “panel of genes” strategy, that offers promising perspectives in the diagnosis and management of neurodegenerative disorders.

Localization of non-receptor tyrosine kinase (nRTK) variants in solid tumor patients using next-generation sequencing (NGS).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1536-1536
Author(s):  
Srishti Sareen ◽  
Matthew Stein ◽  
Lindsay Kaye Morris ◽  
Saradasri Karri ◽  
Kruti Patel ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
In Silico ◽  
Predictive Biomarkers ◽  
In Silico Analysis ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Tumor Patients ◽  
Next Generation Sequencing Ngs ◽  
Silico Analysis ◽  
Generation Sequencing

1536 Background: Non-synonymous SNPs (nsSNPs) in nRTKs may serve as oncologic targets and predictive biomarkers, with significant lesions described in various nRTK regions including the tyrosine kinase domain (TKD). NGS allows the entire coding sequence to be evaluated, facilitating the identification of novel lesions. Methods: We searched all nsSNPs in 14 nRTKs in the tumors of patients (pts) at our institution that received NGS with Caris from 2013-2015 with a diagnosis of advanced breast, colon or lung cancer. Substitutions were classified as either within or extra-TKD; in the case of JAK1-3, pseudokinase domain lesions were also identified. In order to predict the pathogenicity of nsSNPs, in silico analysis with PolyPhen-2 (Harvard) was completed. Results: 356 pts (79 breast, 110 colon and 165 lung (156 NSCLC, 11 small cell)) were identified with a median age of 61 years (range 26-86); 58% female; 62% white, 35% black. 245 variants were found, with 200 nsSNPs and 45 known pathologic mutations (Pmut); Pmut were PIK3CA (21 breast, 13 colon, 5 NSCLC) and AKT1 (6 breast). 169/356 (47%) pts had ≥1 nRTK lesion (0-8). 52/200 (26%) nsSNPs were predicted-damaging (pnsSNPs) with in silico analysis among 49 pts (6 breast, 13 colon and 30 NSCLC). pnsSNPs were found in 14/14 nRTKs with median 3 (1-10). The most frequently mutated nRTKs in breast were SRC (2/2 variants were pnsSNPs) and ABL2 (1/5); in colon ABL1 (5/10), JAK3 (3/27) and CDK12 (2/8); and in NSCLC JAK3 (6/20), BTK (5/8), ABL1 (3/12), JAK2 (3/11), CDK12 (3/9) and JAK1 (3/3). Of 180 nsSNPs with in silico results, 68% were extra-TKD (29/122 variants were pnsSNPs), 23% within the TKD (13/42) and 9% in pseudokinase domains of JAK1-3 (10/16). Notably, 8/10 pseudokinase domain pnsSNPs were in NSCLC pts (3 JAK1, 2 JAK2 and 3 JAK3). Conclusions: > 13% solid tumors held an nRTK nsSNP that was predicted-damaging by in silico analysis, with 69% of these mutations occurring outside of the TKD-proper. Further work is needed to determine how these pnsSNPs affect function and if they are clinically actionable.

scholarly journals A Targeted Gene Panel for Circulating Tumor DNA Sequencing in Neuroblastoma

2020 ◽  
Vol 10 ◽  
Author(s):  
Flora Cimmino ◽  
Vito Alessandro Lasorsa ◽  
Simona Vetrella ◽  
Achille Iolascon ◽  
Mario Capasso
Keyword(s):  
Ad Hoc ◽  
Circulating Tumor Dna ◽  
Gene Panel ◽  
Liquid Biopsies ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variation ◽  
Targeted Ngs ◽  
Molecular Landscape ◽  
Next Generation Sequencing Ngs ◽  
Tumor Biopsies

BackgroundLiquid biopsies do not reflect the complete mutation profile of the tumor but have the potential to identify actionable mutations when tumor biopsies are not available as well as variants with low allele frequency. Most retrospective studies conducted in small cohorts of pediatric cancers have illustrated that the technology yield substantial potential in neuroblastoma.AimThe molecular landscape of neuroblastoma harbors potentially actionable genomic alterations. We aimed to study the utility of liquid biopsy to characterize the mutational landscape of primary neuroblastoma using a custom gene panel for ctDNA targeted sequencing.MethodsTargeted next-generation sequencing (NGS) was performed on ctDNA of 11 patients with primary neuroblastoma stage 4. To avoid the detection of false variants, we used UMIs (unique molecular identifiers) for the library construction, increased the sequencing depth and developed ad hoc bioinformatic analyses including the hard filtering of the variant calls.ResultsWe identified 9/11 (81.8%) patients who carry at least one pathogenic variation. The most frequently mutated genes were KMT2C (five cases), NOTCH1/2 (four cases), CREBBP (three cases), ARID1A/B (three cases), ALK (two cases), FGFR1 (two cases), FAT4 (two cases) and CARD11 (two cases).ConclusionsWe developed a targeted NGS approach to identify tumor-specific alterations in ctDNA of neuroblastoma patients. Our results show the reliability of our approach to generate genomic information which can be integrated with clinical and pathological data at diagnosis.

scholarly journals A Customized Next-Generation Sequencing-Based Panel to Identify Novel Genetic Variants in Dementing Disorders: A Pilot Study

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Giuseppe Lanza ◽  
Francesco Calì ◽  
Mirella Vinci ◽  
Filomena Irene Ilaria Cosentino ◽  
Mariangela Tripodi ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Genetic Variants ◽  
Ad Hoc ◽  
Cognitive Disorders ◽  
High Sensitivity ◽  
Future Application ◽  
Next Generation ◽  
Wide Range ◽  
Gene Panels ◽  
Generation Sequencing

Purpose. The advancements in the next-generation sequencing (NGS) techniques have allowed for rapid, efficient, and cost-time-effective genetic variant detection. However, in both clinical practice and research setting, sequencing is still often limited to the use of gene panels clinically targeted on the genes underlying the disease of interest. Methods. We performed a neurogenetic study through an ad hoc NGS-based custom sequencing gene panel in order to screen 16 genes in 8 patients with different types of degenerative cognitive disorders (Alzheimer’s disease, mild cognitive impairment, frontotemporal dementia, and dementia associated with Parkinson’s disease). The study protocol was based on previous evidence showing a high sensitivity and specificity of the technique even when the panel is limited to some hotspot exons. Results. We found variants of the TREM2 and APP genes in three patients; these have been previously identified as pathogenic or likely pathogenic and, therefore, considered “disease causing.” In the remaining subjects, the pathogenicity was evaluated according to the guidelines of the American College of Medical Genetics (ACMG). In one patient, the p.R205W variant in the CHMP2B gene was found to be likely pathogenic of the disease. A variant in the CSF1R and SERPINI1 genes found in two patients was classified as benign, whereas the other two (in the GRN and APP genes) were classified as likely pathogenic according to the ACMG. Conclusions. Notwithstanding the preliminary value of this study, some rare genetic variants with a probable disease association were detected. Although future application of NGS-based sensors and further replication of these experimental data are needed, this approach seems to offer promising translational perspectives in the diagnosis and management of a wide range of neurodegenerative disorders.

scholarly journals FUNCTIONAL IN SILICO ANALYSIS OF GENETIC VARIANTS FROM GENOME-WIDE ASSOCIATION STUDIES OF BLOOD PRESSURE AND HYPERTENSION

2021 ◽  
Vol 39 (Supplement 1) ◽  
pp. e260-e261
Author(s):  
Sanjeev Pramanik ◽  
Xiao Jiang ◽  
James Eales ◽  
Xiaoguang Xu ◽  
Sushant Saluja ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Genetic Variants ◽  
In Silico ◽  
Association Studies ◽  
In Silico Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Silico Analysis

4101Identification of genetic variants associated with the cardiovascular disease risk factor, low aerobic fitness - The HUNT study

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Bye ◽  
E Ryeng ◽  
J J Silva ◽  
J B Moreira ◽  
D Stensvold ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Risk Factor ◽  
Genetic Variants ◽  
In Silico ◽  
Validation Cohort ◽  
In Silico Analysis ◽  
Candidate Snps ◽  
Cumulative Number ◽  
Wild Card ◽  
Silico Analysis

Abstract Abstract Background: Low maximal oxygen uptake (VO2max) is a strong and independent risk factor for all-cause and cardiovascular disease (CVD) mortality. Although physical activity is a major determinant of VO2maxlevel, genetics contribution is estimated to be ∼50%. Methods We performed a genetic association study on 123.545 single-nucleotide polymorphisms (SNPs) and directly measured VO2max in 3470 individuals (exploration cohort). The candidate SNPs were subsequently analyzed in a separate cohort of 718 individuals (validation cohort), in addition to 7 wild-card SNPs previously associated with VO2max, but not included on the chip used in the exploration cohort. Sub-analyses were performed for each gender. In silico analysis and genotype-phenotype databases were used to predict physiological function of the SNPs. Results In the exploration cohort, 42 SNPs were associated with VO2max (p<5.0×10–4). Six of the candidate SNPs were also found to be associated with VO2max in the validation cohort (p<0.05, either in men, women or both), in addition to three wild-card SNPs. By using these nine SNPs we created a genetic score for inborn VO2max-level. Together, these nine SNPs explained ∼8% of the variation in VO2max, and discriminate individuals with inborn high versus low VO2max based on simultaneous carriage of multiple favorable alleles. The cumulative number of favorable SNPs correlated negatively with the presence of several CVDrisk factors, e.g. waist-circumference, visceral fat, fat %, cholesterol levels and BMI. In silico analysis indicated that several of the SNPs influence gene expression across multiple organs, including adipose tissue, skeletal muscle and heart. Conclusion We identified six novel genetic variants associated with VO2max, and validated three SNPs previously associated with fitness related traits. Acknowledgement/Funding K.G. Jebsen Foundation, the Norwegian Health Association, the Liaison Committee between the Central Norway Regional Health Authority (RHA) and NTNU

In-Silico Analysis of Gene ALS2 Genetic Variants Identified in the Affected Horses and Humans With Motor Neuron Disease

2018 ◽  
Vol 62 ◽  
pp. 60-65
Author(s):  
Shakeela Daud ◽  
Nisar Ahmed ◽  
Sara Naudhani ◽  
Muhammad Younus ◽  
Saba Manzoor ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Genetic Variants ◽  
In Silico ◽  
In Silico Analysis ◽  
Silico Analysis

A systematic review with in silico analysis on transcriptomic profile of gallbladder carcinoma

2020 ◽  
Vol 47 (6) ◽  
pp. 398-408
Author(s):  
Sonam Tulsyan ◽  
Showket Hussain ◽  
Balraj Mittal ◽  
Sundeep Singh Saluja ◽  
Pranay Tanwar ◽  
...  
Keyword(s):  
Systematic Review ◽  
Gallbladder Carcinoma ◽  
In Silico ◽  
In Silico Analysis ◽  
Transcriptomic Profile ◽  
Silico Analysis
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