scholarly journals Exonic variants of genes related to the vitamin D signaling pathway in the families of familial multiple sclerosis using whole‐exome next generation sequencing

2019 ◽  
Vol 9 (4) ◽  
pp. e01272 ◽  
Author(s):  
Vanesa Pytel ◽  
Jordi A. Matías‐Guiu ◽  
Laura Torre‐Fuentes ◽  
Paloma Montero‐Escribano ◽  
Paolo Maietta ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Next Generation Sequencing ◽  
Signaling Pathway ◽  
Next Generation ◽  
Whole Exome ◽  
Vitamin D Signaling ◽  
Generation Sequencing

scholarly journals Deconstruction of HLA-DRB1*04:01:01 and HLA-DRB1*15:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis

2018 ◽  
Vol 25 (6) ◽  
pp. 772-782 ◽  
Author(s):  
Lisa E Creary ◽  
Kalyan C Mallempati ◽  
Sridevi Gangavarapu ◽  
Stacy J Caillier ◽  
Jorge R Oksenberg ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Next Generation Sequencing ◽  
Class Ii ◽  
Effect Sizes ◽  
Molecular Architecture ◽  
Next Generation ◽  
European Americans ◽  
Resolution Level ◽  
Hla Dqa1 ◽  
Generation Sequencing

Background: The association between HLA-DRB1*15:01 with multiple sclerosis (MS) susceptibility is well established, but the contribution of the tightly associated HLA-DRB5*01:01 allele has not yet been completely ascertained. Similarly, the effects of HLA-DRB1*04:01 alleles and haplotypes, defined at the full-gene resolution level with MS risk remains to be elucidated. Objectives: To characterize the molecular architecture of class II HLA-DR15 and HLA-DR4 haplotypes associated with MS. Methods: Next-generation sequencing was used to determine HLA-DQB1, HLA-DQA1, and HLA-DRB1/4/5 alleles in 1403 unrelated European-American patients and 1425 healthy unrelated controls. Effect sizes of HLA alleles and haplotypes on MS risk were measured by odds ratio (OR) with 95% confidence intervals. Results: HLA-DRB1*15:01:01:01SG (OR = 3.20, p < 2.2E–16), HLA-DRB5*01:01:01 (OR = 2.96, p < 2.2E–16), and HLA-DRB5*01:01:01v1_STR1 (OR = 8.18, p = 4.3E–05) alleles all occurred at significantly higher frequencies in MS patients compared to controls. The most significant predis-posing haplotypes were HLA-DQB1*06:02:01~ HLA-DQA1*01:02:01:01SG~HLA-DRB1*15:01:01:01SG~HLA-DRB5*01:01:01 and HLA-DQB1*06:02:01~HLA-DQA1*01:02:01:01SG~HLA-DRB1*15:01:01:01SG~HLA-DRB5*01:01:01v1_STR1 (OR = 3.19, p < 2.2E–16; OR = 9.30, p = 9.7E–05, respectively). Analyses of the HLA-DRB1*04 cohort in the absence of HLA-DRB1*15:01 haplotypes revealed that the HLA-DQB1*03:01:01:01~HLA-DQA1*03:03:01:01~HLA-DRB1*04:01:01:01SG~HLA-DRB4*01:03:01:01 haplotype was protective (OR = 0.64, p = 0.028), whereas the HLA-DQB1*03:02:01~HLA-DQA1*03:01:01~HLA-DRB1*04:01:01:01SG~HLA-DRB4*01:03:01:01 haplotype was associated with MS susceptibility (OR = 1.66, p = 4.9E–03). Conclusion: HLA-DR15 haplotypes, including genomic variants of HLA-DRB5, and HLA-DR4 haplotypes affect MS risk.

scholarly journals Next Generation Sequencing Identifies Five Novel Mutations in Lebanese Patients with Bardet–Biedl and Usher Syndromes

Genes ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 1047 ◽  
Author(s):  
Lama Jaffal ◽  
Wissam H Joumaa ◽  
Alexandre Assi ◽  
Charles Helou ◽  
George Cherfan ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Usher Syndrome ◽  
Bioinformatic Analysis ◽  
Next Generation ◽  
Novel Mutations ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Targeted Ngs ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Aim: To identify disease-causing mutations in four Lebanese families: three families with Bardet–Biedl and one family with Usher syndrome (BBS and USH respectively), using next generation sequencing (NGS). Methods: We applied targeted NGS in two families and whole exome sequencing (WES) in two other families. Pathogenicity of candidate mutations was evaluated according to frequency, conservation, in silico prediction tools, segregation with disease, and compatibility with inheritance pattern. The presence of pathogenic variants was confirmed via Sanger sequencing followed by segregation analysis. Results: Most likely disease-causing mutations were identified in all included patients. In BBS patients, we found (M1): c.2258A > T, p. (Glu753Val) in BBS9, (M2): c.68T > C; p. (Leu23Pro) in ARL6, (M3): c.265_266delTT; p. (Leu89Valfs*11) and (M4): c.880T > G; p. (Tyr294Asp) in BBS12. A previously known variant (M5): c.551A > G; p. (Asp184Ser) was also detected in BBS5. In the USH patient, we found (M6): c.188A > C, p. (Tyr63Ser) in CLRN1. M2, M3, M4, and M6 were novel. All of the candidate mutations were shown to be likely disease-causing through our bioinformatic analysis. They also segregated with the corresponding phenotype in available family members. Conclusion: This study expanded the mutational spectrum and showed the genetic diversity of BBS and USH. It also spotlighted the efficiency of NGS techniques in revealing mutations underlying clinically and genetically heterogeneous disorders.

scholarly journals MSPrecise: A molecular diagnostic test for multiple sclerosis using next generation sequencing

Gene ◽  
2015 ◽  
Vol 572 (2) ◽  
pp. 191-197 ◽  
Author(s):  
William H. Rounds ◽  
Edward A. Salinas ◽  
Tom B. Wilks ◽  
Mikhail K. Levin ◽  
Ann J. Ligocki ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Next Generation Sequencing ◽  
Diagnostic Test ◽  
Molecular Diagnostic ◽  
Next Generation ◽  
Molecular Diagnostic Test ◽  
Generation Sequencing

scholarly journals Molekuláris genetikai vizsgálatok primer immundefektusokban

2018 ◽  
Vol 159 (49) ◽  
pp. 2095-2112
Author(s):  
Melinda Erdős
Keyword(s):  
Next Generation Sequencing ◽  
Primary Immunodeficiency ◽  
Molecular Genetic ◽  
Primary Immunodeficiencies ◽  
Genetic Diagnostics ◽  
Next Generation ◽  
Advantages And Disadvantages ◽  
Whole Exome ◽  
Molecular Genetic Diagnostics ◽  
Generation Sequencing

Abstract: Next generation sequencing methods represent the latest era of molecular genetic diagnostics. After a general introduction on primary immunodeficiencies, the author summarizes the importance of molecular genetic studies, especially next generation sequencing in the diagnosis of primary immunodeficiencies. Another purpose of the manuscript is to give a brief summary on the methodological basis of next generation sequencing. The author analyzes the advantages and disadvantages of primary immunodeficiency gene-panel sequencing and whole-exome and whole-genome sequencing. Primary immunodeficiency genes and diseases recognized by next generation sequencing is also summarized. Finally, the author emphasizes the indispensability of gene level diagnostics in primary immunodeficiencies and presents the results achieved in this field in Hungary. Orv Hetil. 2018; 159(49): 2095–2112.

scholarly journals Finding functional disease-associated non-coding variation using next-generation sequencing

2016 ◽  
Author(s):  
Paolo Devanna ◽  
Xiaowei Sylvia Chen ◽  
Joses Ho ◽  
Dario Gajewski ◽  
Alessandro Gialluisi ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Binding Sites ◽  
Large Scale ◽  
Sequence Data ◽  
Whole Genome Sequence ◽  
Next Generation Sequencing Data ◽  
Whole Genome ◽  
Next Generation ◽  
Whole Exome ◽  
Generation Sequencing

ABSTRACTNext generation sequencing has opened the way for the large scale interrogation of cohorts at the whole exome, or whole genome level. Currently, the field largely focuses on potential disease causing variants that fall within coding sequences and that are predicted to cause protein sequence changes, generally discarding non-coding variants. However non-coding DNA makes up ~98% of the genome and contains a range of sequences essential for controlling the expression of protein coding genes. Thus, potentially causative non-coding variation is currently being overlooked. To address this, we have designed an approach to assess variation in one class of non-coding regulatory DNA; the 3′UTRome. Variants in the 3'UTR region of genes are of particular interest because 3'UTRs are responsible for modulating protein expression levels via their interactions with microRNAs. Furthermore they are amenable to large scale analysis as 3′UTR-microRNA interactions are based on complementary base pairing and as such can be predicted in silico at the genome-wide level. We report a strategy for identifying and functionally testing variants in microRNA binding sites within the 3'UTRome and demonstrate the efficacy of this pipeline in a cohort of language impaired children. Using whole exome sequence data from 43 probands, we extracted variants that lay within 3'UTR microRNA binding sites. We identified a common variant (SNP) in a microRNA binding site and found this SNP to be associated with an endophenotype of language impairment (non-word repetition). We showed that this variant disrupted microRNA regulation in cells and was linked to altered gene expression in the brain, suggesting it may represent a risk factor contributing to SLI. This work demonstrates that biologically relevant variants are currently being under-investigated despite the wealth of next-generation sequencing data available and presents a simple strategy for interrogating non-coding regions of the genome. We propose that this strategy should be routinely applied to whole exome and whole genome sequence data in order to broaden our understanding of how non-coding genetic variation underlies complex phenotypes such as neurodevelopmental disorders.

scholarly journals Whole Exome Sequencing Reveals Genetic Predisposition in a Large Family with Retinitis Pigmentosa

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Juan Wu ◽  
Lijia Chen ◽  
Oi Sin Tam ◽  
Xiu-Feng Huang ◽  
Chi-Pui Pang ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Retinitis Pigmentosa ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Direct Sequencing ◽  
Genetic Defect ◽  
Chinese Family ◽  
Next Generation ◽  
Whole Exome ◽  
Generation Sequencing

Next-generation sequencing has become more widely used to reveal genetic defect in monogenic disorders. Retinitis pigmentosa (RP), the leading cause of hereditary blindness worldwide, has been attributed to more than 67 disease-causing genes. Due to the extreme genetic heterogeneity, using general molecular screening alone is inadequate for identifying genetic predispositions in susceptible individuals. In order to identify underlying mutation rapidly, we utilized next-generation sequencing in a four-generation Chinese family with RP. Two affected patients and an unaffected sibling were subjected to whole exome sequencing. Through bioinformatics analysis and direct sequencing confirmation, we identified p.R135W transition in the rhodopsin gene. The mutation was subsequently confirmed to cosegregate with the disease in the family. In this study, our results suggest that whole exome sequencing is a robust method in diagnosing familial hereditary disease.

MSI-WES: a simple approach for microsatellite instability testing using whole exome sequencing

2021 ◽  
Author(s):  
Henry O Ebili ◽  
Adedeji OJ Agboola ◽  
Emad Rakha
Keyword(s):  
Next Generation Sequencing ◽  
Microsatellite Instability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Methylation Status ◽  
Molecular Targets ◽  
Next Generation ◽  
Variant Call ◽  
Whole Exome ◽  
Generation Sequencing

Aim: To demonstrate that MSI-WES is an accurate testing method for microsatellite instability (MSI). Materials & methods: Microsatellite-based indels were counted in the variant call-formatted whole exome sequencing (WES) data of 441 gastric cancer cases using Unix-based algorithms, and the counts expressed as a fraction of the genome sequenced to obtain next-generation sequencing-based MSI indices. Results: The next-generation sequencing-based MSI indices showed a near-perfect concordance with PCR-based MSI status, and moderate to good correlations with the molecular targets of MSI index, MLH1 expression and MLH1 methylation status, at a level comparable to the strengths of correlation between PCR-based MSI status and molecular targets of MSI index/ MLH1 expression and methylation. Conclusion: MSI-WES is a valid, adequate and sensitive approach for testing MSI in cancer.

scholarly journals Whole-Exome Sequencing for Diagnosis of Turner Syndrome: Toward Next-Generation Sequencing and Newborn Screening

2017 ◽  
Vol 102 (5) ◽  
pp. 1529-1537 ◽  
Author(s):  
David R. Murdock ◽  
Frank X. Donovan ◽  
Settara C. Chandrasekharappa ◽  
Nicole Banks ◽  
Carolyn Bondy ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Newborn Screening ◽  
Exome Sequencing ◽  
Turner Syndrome ◽  
Whole Exome Sequencing ◽  
Genomic Research ◽  
Next Generation ◽  
Low Level ◽  
Whole Exome ◽  
Generation Sequencing

Abstract Context: Turner syndrome (TS) is due to a complete or partial loss of an X chromosome in female patients and is not currently part of newborn screening (NBS). Diagnosis is often delayed, resulting in missed crucial diagnostic and therapeutic opportunities. Objectives: This study sought to determine if whole-exome sequencing (WES) as part of a potential NBS program could be used to diagnose TS. Design, Setting, Patients: Karyotype, chromosomal microarray, and WES were performed on blood samples from women with TS (n = 27) enrolled in the Personalized Genomic Research study at the National Institutes of Health. Female control subjects (n = 37) and male subjects (n = 27) also underwent WES. Copy number variation was evaluated using EXCAVATOR2 and B allele frequency was calculated from informative single nucleotide polymorphisms. Simulated WES data were generated for detection of low-level mosaicism and complex structural chromosome abnormalities. Results: We detected monosomy for chromosome X in all 27 TS samples, including 1 mosaic for 45,X/46,XX and another with previously unreported material on chromosome Y. Sensitivity and specificity were both 100% for the diagnosis of TS with no false-positive or false-negative results. Using simulated WES data, we detected isochromosome Xq and low-level mosaicism as low as 5%. Conclusion: We present an accurate method of diagnosing TS using WES, including cases with low-level mosaicism, isochromosome Xq, and cryptic Y-chromosome material. Given the potential use of next-generation sequencing for NBS in many different diseases and syndromes, we propose WES can be used as a screening test for TS in newborns.

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