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variant calling exome

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https://www.readbyqxmd.com/read/27899611/the-exac-browser-displaying-reference-data-information-from-over-60-000-exomes
#1
Konrad J Karczewski, Ben Weisburd, Brett Thomas, Matthew Solomonson, Douglas M Ruderfer, David Kavanagh, Tymor Hamamsy, Monkol Lek, Kaitlin E Samocha, Beryl B Cummings, Daniel Birnbaum, Mark J Daly, Daniel G MacArthur
Worldwide, hundreds of thousands of humans have had their genomes or exomes sequenced, and access to the resulting data sets can provide valuable information for variant interpretation and understanding gene function. Here, we present a lightweight, flexible browser framework to display large population datasets of genetic variation. We demonstrate its use for exome sequence data from 60 706 individuals in the Exome Aggregation Consortium (ExAC). The ExAC browser provides gene- and transcript-centric displays of variation, a critical view for clinical applications...
November 28, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27896285/rare-variants-in-optic-disc-area-gene-card10-enriched-in-primary-open-angle-glaucoma
#2
Tiger Zhou, Emmanuelle Souzeau, Shiwani Sharma, Owen M Siggs, Ivan Goldberg, Paul R Healey, Stuart Graham, Alex W Hewitt, David A Mackey, Robert J Casson, John Landers, Richard Mills, Jonathan Ellis, Paul Leo, Matthew A Brown, Stuart MacGregor, Kathryn P Burdon, Jamie E Craig
BACKGROUND: Genome-wide association studies (GWAS) have identified association of common alleles with primary open-angle glaucoma (POAG) and its quantitative endophenotypes near numerous genes. This study aims to determine whether rare pathogenic variants in these disease-associated genes contribute to POAG. METHODS: Participants fulfilled strict inclusion criteria of advanced POAG at a young age of diagnosis. Myocilin mutation carriers were excluded using direct sequencing...
November 2016: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/27888232/parents-perspectives-on-whole-genome-sequencing-for-their-children-qualified-enthusiasm
#3
J A Anderson, M S Meyn, C Shuman, R Zlotnik Shaul, L E Mantella, M J Szego, S Bowdin, N Monfared, R Z Hayeems
OBJECTIVE: To better understand the consequences of returning whole genome sequencing (WGS) results in paediatrics and facilitate its evidence-based clinical implementation, we studied parents' experiences with WGS and their preferences for the return of adult-onset secondary variants (SVs)-medically actionable genomic variants unrelated to their child's current medical condition that predict adult-onset disease. METHODS: We conducted qualitative interviews with parents whose children were undergoing WGS as part of the SickKids Genome Clinic, a research project that studies the impact of clinical WGS on patients, families, and the healthcare system...
November 25, 2016: Journal of Medical Ethics
https://www.readbyqxmd.com/read/27874022/in-depth-comparison-of-somatic-point-mutation-callers-based-on-different-tumor-next-generation-sequencing-depth-data
#4
Lei Cai, Wei Yuan, Zhou Zhang, Lin He, Kuo-Chen Chou
Four popular somatic single nucleotide variant (SNV) calling methods (Varscan, SomaticSniper, Strelka and MuTect2) were carefully evaluated on the real whole exome sequencing (WES, depth of ~50X) and ultra-deep targeted sequencing (UDT-Seq, depth of ~370X) data. The four tools returned poor consensus on candidates (only 20% of calls were with multiple hits by the callers). For both WES and UDT-Seq, MuTect2 and Strelka obtained the largest proportion of COSMIC entries as well as the lowest rate of dbSNP presence and high-alternative-alleles-in-control calls, demonstrating their superior sensitivity and accuracy...
November 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27862228/exome-copy-number-variation-detection-use-of-a-pool-of-unrelated-healthy-tissue-as-reference-sample
#5
Stephane Wenric, Tiberio Sticca, Jean-Hubert Caberg, Claire Josse, Corinne Fasquelle, Christian Herens, Mauricette Jamar, Stéphanie Max, André Gothot, Jo Caers, Vincent Bours
An increasing number of bioinformatic tools designed to detect CNVs (copy number variants) in tumor samples based on paired exome data where a matched healthy tissue constitutes the reference have been published in the recent years. The idea of using a pool of unrelated healthy DNA as reference has previously been formulated but not thoroughly validated. As of today, the gold standard for CNV calling is still aCGH but there is an increasing interest in detecting CNVs by exome sequencing. We propose to design a metric allowing the comparison of two CNV profiles, independently of the technique used and assessed the validity of using a pool of unrelated healthy DNA instead of a matched healthy tissue as reference in exome-based CNV detection...
November 10, 2016: Genetic Epidemiology
https://www.readbyqxmd.com/read/27854363/indel-variant-analysis-of-short-read-sequencing-data-with-scalpel
#6
Han Fang, Ewa A Bergmann, Kanika Arora, Vladimir Vacic, Michael C Zody, Ivan Iossifov, Jason A O'Rawe, Yiyang Wu, Laura T Jimenez Barron, Julie Rosenbaum, Michael Ronemus, Yoon-Ha Lee, Zihua Wang, Esra Dikoglu, Vaidehi Jobanputra, Gholson J Lyon, Michael Wigler, Michael C Schatz, Giuseppe Narzisi
As the second most common type of variation in the human genome, insertions and deletions (indels) have been linked to many diseases, but the discovery of indels of more than a few bases in size from short-read sequencing data remains challenging. Scalpel (http://scalpel.sourceforge.net) is an open-source software for reliable indel detection based on the microassembly technique. It has been successfully used to discover mutations in novel candidate genes for autism, and it is extensively used in other large-scale studies of human diseases...
December 2016: Nature Protocols
https://www.readbyqxmd.com/read/27842494/snooper-a-machine-learning-based-method-for-somatic-variant-identification-from-low-pass-next-generation-sequencing
#7
Jean-François Spinella, Pamela Mehanna, Ramon Vidal, Virginie Saillour, Pauline Cassart, Chantal Richer, Manon Ouimet, Jasmine Healy, Daniel Sinnett
BACKGROUND: Next-generation sequencing (NGS) allows unbiased, in-depth interrogation of cancer genomes. Many somatic variant callers have been developed yet accurate ascertainment of somatic variants remains a considerable challenge as evidenced by the varying mutation call rates and low concordance among callers. Statistical model-based algorithms that are currently available perform well under ideal scenarios, such as high sequencing depth, homogeneous tumor samples, high somatic variant allele frequency (VAF), but show limited performance with sub-optimal data such as low-pass whole-exome/genome sequencing data...
November 14, 2016: BMC Genomics
https://www.readbyqxmd.com/read/27828722/genetics-of-combined-pituitary-hormone-deficiency-roadmap-into-the-genome-era
#8
Qing Fang, Akima S George, Michelle L Brinkmeier, Amanda H Mortensen, Peter Gergics, Leonard Y M Cheung, Alexandre Z Daly, Adnan Ajmal, María Ines Pérez Millán, A Bilge Ozel, Jacob O Kitzman, Ryan E Mills, Jun Z Li, Sally A Camper
The genetic basis for combined pituitary hormone deficiency (CPHD) is complex, involving 30 genes in a variety of syndromic and nonsyndromic presentations. Molecular diagnosis of this disorder is valuable for predicting disease progression, avoiding unnecessary surgery, and family planning. We expect that the application of high throughput sequencing will uncover additional contributing genes and eventually become a valuable tool for molecular diagnosis. For example, in the last three years, six new genes have been implicated in CPHD using whole exome sequencing (WES)...
November 9, 2016: Endocrine Reviews
https://www.readbyqxmd.com/read/27807805/identification-of-heterozygous-single-and-multi-exon-deletions-in-il7r-by-whole-exome-sequencing
#9
Karin R Engelhardt, Yaobo Xu, Angela Grainger, Mila G C Germani Batacchi, David J Swan, Joseph D P Willet, Intan J Abd Hamid, Philipp Agyeman, Dawn Barge, Shahnaz Bibi, Lucy Jenkins, Terence J Flood, Mario Abinun, Mary A Slatter, Andrew R Gennery, Andrew J Cant, Mauro Santibanez Koref, Kimberly Gilmour, Sophie Hambleton
PURPOSE: We aimed to achieve a retrospective molecular diagnosis by applying state-of-the-art genomic sequencing methods to past patients with T-B+NK+ severe combined immunodeficiency (SCID). We included identification of copy number variations (CNVs) by whole exome sequencing (WES) using the CNV calling method ExomeDepth to detect gene alterations for which routine Sanger sequencing analysis is not suitable, such as large heterozygous deletions. METHODS: Of a total of 12 undiagnosed patients with T-B+NK+ SCID, we analyzed eight probands by WES, using GATK to detect single nucleotide variants (SNVs) and small insertions and deletions (INDELs) and ExomeDepth to detect CNVs...
November 2, 2016: Journal of Clinical Immunology
https://www.readbyqxmd.com/read/27804958/dominant-variants-in-the-splicing-factor-puf60-cause-a-recognizable-syndrome-with-intellectual-disability-heart-defects-and-short-stature
#10
Salima El Chehadeh, Wilhelmina S Kerstjens-Frederikse, Julien Thevenon, Paul Kuentz, Ange-Line Bruel, Christel Thauvin-Robinet, Candace Bensignor, Hélène Dollfus, Vincent Laugel, Jean-Baptiste Rivière, Yannis Duffourd, Caroline Bonnet, Matthieu P Robert, Rodica Isaiko, Morgane Straub, Catherine Creuzot-Garcher, Patrick Calvas, Nicolas Chassaing, Bart Loeys, Edwin Reyniers, Geert Vandeweyer, Frank Kooy, Miroslava Hančárová, Marketa Havlovicová, Darina Prchalová, Zdenek Sedláček, Christian Gilissen, Rolph Pfundt, Jolien S Klein Wassink-Ruiter, Laurence Faivre
Verheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype...
November 2, 2016: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/27798045/whole-exome-sequencing-of-familial-cases-of-multiple-morphological-abnormalities-of-the-sperm-flagella-mmaf-reveals-new-dnah1-mutations
#11
Amir Amiri-Yekta, Charles Coutton, Zine-Eddine Kherraf, Thomas Karaouzène, Pauline Le Tanno, Mohammad Hossein Sanati, Marjan Sabbaghian, Navid Almadani, Mohammad Ali Sadighi Gilani, Seyedeh Hanieh Hosseini, Salahadin Bahrami, Abbas Daneshipour, Maurizio Bini, Christophe Arnoult, Roberto Colombo, Hamid Gourabi, Pierre F Ray
STUDY QUESTION: Can whole-exome sequencing (WES) of patients with multiple morphological abnormalities of the sperm flagella (MMAF) identify causal mutations in new genes or mutations in the previously identified dynein axonemal heavy chain 1 (DNAH1) gene? SUMMARY ANSWER: WES for six families with men affected by MMAF syndrome allowed the identification of DNAH1 mutations in four affected men distributed in two out of the six families but no new candidate genes were identified...
October 26, 2016: Human Reproduction
https://www.readbyqxmd.com/read/27720020/exome-and-genome-sequencing-for-inborn-errors-of-immunity
#12
REVIEW
Isabelle Meyts, Barbara Bosch, Alexandre Bolze, Bertrand Boisson, Yuval Itan, Aziz Belkadi, Vincent Pedergnana, Leen Moens, Capucine Picard, Aurélie Cobat, Xavier Bossuyt, Laurent Abel, Jean-Laurent Casanova
The advent of next-generation sequencing (NGS) in 2010 has transformed medicine, particularly the growing field of inborn errors of immunity. NGS has facilitated the discovery of novel disease-causing genes and the genetic diagnosis of patients with monogenic inborn errors of immunity. Whole-exome sequencing (WES) is presently the most cost-effective approach for research and diagnostics, although whole-genome sequencing offers several advantages. The scientific or diagnostic challenge consists in selecting 1 or 2 candidate variants among thousands of NGS calls...
October 2016: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27716037/impact-of-post-alignment-processing-in-variant-discovery-from-whole-exome-data
#13
Shulan Tian, Huihuang Yan, Michael Kalmbach, Susan L Slager
BACKGROUND: GATK Best Practices workflows are widely used in large-scale sequencing projects and recommend post-alignment processing before variant calling. Two key post-processing steps include the computationally intensive local realignment around known INDELs and base quality score recalibration (BQSR). Both have been shown to reduce erroneous calls; however, the findings are mainly supported by the analytical pipeline that incorporates BWA and GATK UnifiedGenotyper. It is not known whether there is any benefit of post-processing and to what extent the benefit might be for pipelines implementing other methods, especially given that both mappers and callers are typically updated...
October 3, 2016: BMC Bioinformatics
https://www.readbyqxmd.com/read/27701467/germline-variants-of-prostate-cancer-in-japanese-families
#14
Takahide Hayano, Hiroshi Matsui, Hirofumi Nakaoka, Nobuaki Ohtake, Kazuyoshi Hosomichi, Kazuhiro Suzuki, Ituro Inoue
Prostate cancer (PC) is the second most common cancer in men. Family history is the major risk factor for PC. Only two susceptibility genes were identified in PC, BRCA2 and HOXB13. A comprehensive search of germline variants for patients with PC has not been reported in Japanese families. In this study, we conducted exome sequencing followed by Sanger sequencing to explore responsible germline variants in 140 Japanese patients with PC from 66 families. In addition to known susceptibility genes, BRCA2 and HOXB13, we identified TRRAP variants in a mutually exclusive manner in seven large PC families (three or four patients per family)...
2016: PloS One
https://www.readbyqxmd.com/read/27687302/pathway-level-alterations-rather-than-mutations-in-single-genes-predict-response-to-her2-targeted-therapies-in-the-neo-altto-trial
#15
W Shi, T Jiang, P Nuciforo, C Hatzis, E Holmes, N Harbeck, C Sotiriou, L Peña, S Loi, D D Rosa, S Chia, A Wardley, T Ueno, J Rossari, H Eidtmann, A Armour, M Piccart-Gebhart, D L Rimm, J Baselga, L Pusztai
BACKGROUND: We performed whole-exome sequencing of pretreatment biopsies and examined whether genome-wide metrics of overall mutational load, clonal heterogeneity or alterations at variant, gene, and pathway levels are associated with treatment response and survival. PATIENTS AND METHODS: Two hundred and three biopsies from the NeoALTTO trial were analyzed. Mutations were called with MuTect, and Strelka, using pooled normal DNA. Associations between DNA alterations and outcome were evaluated by logistic and Cox-proportional hazards regression...
September 29, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27626065/a-novel-tp53-kpna3-translocation-defines-a-de-novo-treatment-resistant-clone-in-osteosarcoma
#16
Kenneth S Chen, Woo Sun Kwon, Jiwoong Kim, Su Jin Heo, Hyo Song Kim, Hyo Ki Kim, Soo Hee Kim, Won Suk Lee, Hyun Cheol Chung, Sun Young Rha, Tae Hyun Hwang
Osteosarcoma is the most common primary bone cancer. It can be cured by aggressive surgery and chemotherapy, but outcomes for metastatic or chemoresistant disease remain dismal. Cancer sequencing studies have shown that the p53 pathway is dysregulated in nearly every case, often by translocation; however, no studies of osteosarcoma evolution or intratumor heterogeneity have been done to date. We studied a patient with chemoresistant, metastatic disease over the course of 3 years. We performed exome sequencing on germline DNA and DNA collected from tumor at three separate time points...
September 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27590916/an-analytical-workflow-for-accurate-variant-discovery-in-highly-divergent-regions
#17
Shulan Tian, Huihuang Yan, Claudia Neuhauser, Susan L Slager
BACKGROUND: Current variant discovery methods often start with the mapping of short reads to a reference genome; yet, their performance deteriorates in genomic regions where the reads are highly divergent from the reference sequence. This is particularly problematic for the human leukocyte antigen (HLA) region on chromosome 6p21.3. This region is associated with over 100 diseases, but variant calling is hindered by the extreme divergence across different haplotypes. RESULTS: We simulated reads from chromosome 6 exonic regions over a wide range of sequence divergence and coverage depth...
2016: BMC Genomics
https://www.readbyqxmd.com/read/27544999/immune-response-associated-gene-analysis-of-1-000-cancer-patients-using-whole-exome-sequencing-and-gene-expression-profiling-project-hope
#18
Yasuto Akiyama, Ryota Kondou, Akira Iizuka, Keiichi Ohshima, Kenichi Urakami, Takeshi Nagashima, Yuji Shimoda, Tomoe Tanabe, Sumiko Ohnami, Shumpei Ohnami, Masatoshi Kusuhara, Tohru Mochizuki, Ken Yamaguchi
Project HOPE (High-tech Omics-based Patient Evaluation) has been progressing since its implementation in 2014 using whole-exome sequencing (WES) and gene expression profiling (GEP). With the aim of evaluating immune status in cancer patients, a gene panel consisting of 164 immune response-associated genes (56 antigen-presenting cell and T-cell-associated genes, 34 cytokine- and metabolism-associated genes, 47 TNF and TNF receptor superfamily genes, and 27 regulatory T-cell-associated genes) was established, and its expression and mutation status were investigated using 1,000 cancer patient-derived tumors...
2016: Biomedical Research
https://www.readbyqxmd.com/read/27499913/genotyping-confirms-inheritance-of-the-rare-at-a-type-in-a-case-of-haemolytic-disease-of-the-newborn
#19
Rhiannon McBean, Yew-Wah Liew, Brett Wilson, Pawinee Kupatawintu, Morakot Emthip, Catherine Hyland, Robert Flower
The At(a) blood group antigen (now AUG2 in the Augustine system) is a high-frequency antigen with negative phenotype At(a-) found only in individuals of African ancestry. In a twin pregnancy, the fifth pregnancy in a woman of African origin, serological investigations confirmed that the mother was At(a-) and anti-At(a) was detected. DNA samples were exome sequenced and alignment was performed to allow variant calling. It was confirmed that the single nucleotide polymorphism, rs45458701, within the SLC29A1 gene encoding the ENT1 protein, recently reported to be a basis of the At(a-) phenotype was also the basis of the phenotype in this family...
January 2016: Journal of Pathology. Clinical Research
https://www.readbyqxmd.com/read/27454357/evaluating-the-necessity-of-pcr-duplicate-removal-from-next-generation-sequencing-data-and-a-comparison-of-approaches
#20
Mark T W Ebbert, Mark E Wadsworth, Lyndsay A Staley, Kaitlyn L Hoyt, Brandon Pickett, Justin Miller, John Duce, John S K Kauwe, Perry G Ridge
BACKGROUND: Analyzing next-generation sequencing data is difficult because datasets are large, second generation sequencing platforms have high error rates, and because each position in the target genome (exome, transcriptome, etc.) is sequenced multiple times. Given these challenges, numerous bioinformatic algorithms have been developed to analyze these data. These algorithms aim to find an appropriate balance between data loss, errors, analysis time, and memory footprint. Typical analysis pipelines require multiple steps...
2016: BMC Bioinformatics
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