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https://www.readbyqxmd.com/read/29776351/a-computational-study-of-hedgehog-signalling-involved-in-basal-cell-carcinoma-reveals-the-potential-and-limitation-of-combination-therapy
#1
Antoine Buetti-Dinh, Rebecca Jensen, Ran Friedman
BACKGROUND: The smoothened (SMO) receptor is an essential component of the Sonic hedgehog (SHH) signalling, which is associated with the development of skin basal cell carcinoma (BCC). SMO inhibitors are indicated for BCC patients when surgical treatment or radiation therapy are not possible. Unfortunately, SMO inhibitors are not always well tolerated due to severe side effects, and their therapeutical success is limited by resistance mutations. METHODS: We investigated how common are resistance-causing mutations in two genomic databases which are not linked to BCC or other cancers, namely 1000 Genomes and ExAC...
May 18, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29764365/towards-pan-genome-read-alignment-to-improve-variation-calling
#2
Daniel Valenzuela, Tuukka Norri, Niko Välimäki, Esa Pitkänen, Veli Mäkinen
BACKGROUND: Typical human genome differs from the reference genome at 4-5 million sites. This diversity is increasingly catalogued in repositories such as ExAC/gnomAD, consisting of >15,000 whole-genomes and >126,000 exome sequences from different individuals. Despite this enormous diversity, resequencing data workflows are still based on a single human reference genome. Identification and genotyping of genetic variants is typically carried out on short-read data aligned to a single reference, disregarding the underlying variation...
May 9, 2018: BMC Genomics
https://www.readbyqxmd.com/read/29761599/analysis-of-the-exome-aggregation-consortium-exac-database-suggests-that-the-bap1-tumor-predisposition-syndrome-is-underreported-in-cancer-patients
#3
James B Massengill, Klarke M Sample, Robert Pilarski, Joseph McElroy, Frederick H Davidorf, Colleen M Cebulla, Mohamed H Abdel-Rahman
The BAP1-tumor predisposition syndrome (BAP1-TPDS) has been recently identified to predispose patients to a variety of cancers and preneoplastic lesions. About 130 unrelated probands have been identified worldwide; however, the impact of the syndrome is suspected to be much larger given the diversity of the cancer phenotype. To evaluate the frequency of germline BAP1 mutations in the general and cancer populations, we analyzed the Exome Aggregation Consortium (ExAC), a database that contains 53105 exomes of unrelated individuals unaffected by cancer (general population) and exomes of 7601 unrelated individuals affected by cancer provided by the Cancer Genome Atlas (TCGA, cancer subjects)...
May 15, 2018: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/29761480/whole-exome-sequencing-identifies-plec-exo5-and-dnah7-as-novel-susceptibility-genes-in-testicular-cancer
#4
Beatriz Paumard-Hernández, Oriol Calvete, Lucia Inglada Pérez, Héctor Tejero, Fátima Al-Shahrour, Guillermo Pita, Alicia Barroso, Juan Carlos Triviño, Miguel Urioste, Claudia Valverde, Enrique González Billalabeitia, Vanesa Quiroga, Juan Francisco Rodríguez Moreno, Antonio Fernández Aramburo, Cristina López, Pablo Maroto, Javier Sastre, María José Juan Fita, Ignacio Duran, Isabel Lorenzo-Lorenzo, Patricia Iranzo, Xavier García Del Muro, Silverio Ros, Francisco Zambrana, Ana María Autran, Javier Benítez
Testicular germ cell tumors (TGCTs) are a clinically and pathologically heterogeneous disease, and little is known of its genetic basis. Only low susceptibility risk loci have been identified for both sporadic and familial cases. Therefore, we tried to identify new susceptibility genes responsible for familial testicular cancer that may contribute to increasing our knowledge about the genetic basis of the disease. Nineteen Spanish families with at least two affected individuals with TGCT were selected. WES was performed on those individuals using an Illumina Hiseq2000 sequencing platform...
May 15, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29753700/spectrum-and-prevalence-of-genetic-predisposition-in-medulloblastoma-a-retrospective-genetic-study-and-prospective-validation-in-a-clinical-trial-cohort
#5
Sebastian M Waszak, Paul A Northcott, Ivo Buchhalter, Giles W Robinson, Christian Sutter, Susanne Groebner, Kerstin B Grund, Laurence Brugières, David T W Jones, Kristian W Pajtler, A Sorana Morrissy, Marcel Kool, Dominik Sturm, Lukas Chavez, Aurelie Ernst, Sebastian Brabetz, Michael Hain, Thomas Zichner, Maia Segura-Wang, Joachim Weischenfeldt, Tobias Rausch, Balca R Mardin, Xin Zhou, Cristina Baciu, Christian Lawerenz, Jennifer A Chan, Pascale Varlet, Lea Guerrini-Rousseau, Daniel W Fults, Wiesława Grajkowska, Peter Hauser, Nada Jabado, Young-Shin Ra, Karel Zitterbart, Suyash S Shringarpure, Francisco M De La Vega, Carlos D Bustamante, Ho-Keung Ng, Arie Perry, Tobey J MacDonald, Pablo Hernáiz Driever, Anne E Bendel, Daniel C Bowers, Geoffrey McCowage, Murali M Chintagumpala, Richard Cohn, Timothy Hassall, Gudrun Fleischhack, Tone Eggen, Finn Wesenberg, Maria Feychting, Birgitta Lannering, Joachim Schüz, Christoffer Johansen, Tina V Andersen, Martin Röösli, Claudia E Kuehni, Michael Grotzer, Kristina Kjaerheim, Camelia M Monoranu, Tenley C Archer, Elizabeth Duke, Scott L Pomeroy, Redmond Shelagh, Stephan Frank, David Sumerauer, Wolfram Scheurlen, Marina V Ryzhova, Till Milde, Christian P Kratz, David Samuel, Jinghui Zhang, David A Solomon, Marco Marra, Roland Eils, Claus R Bartram, Katja von Hoff, Stefan Rutkowski, Vijay Ramaswamy, Richard J Gilbertson, Andrey Korshunov, Michael D Taylor, Peter Lichter, David Malkin, Amar Gajjar, Jan O Korbel, Stefan M Pfister
BACKGROUND: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. METHODS: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED)...
May 9, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29749507/identification-of-chchd2-mutations-in-patients-with-alzheimer-s-disease-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia-in-china
#6
Xixi Liu, Bin Jiao, Weiwei Zhang, Tingting Xiao, Lihua Hou, Chuzheng Pan, Beisha Tang, Lu Shen
Recently, the coiled‑coil‑helix‑coiled‑coil‑helix domain 2 (CHCHD2) gene was identified as a possible causative gene for Parkinson's disease (PD). Three other neurodegenerative diseases, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), share significant overlaps with PD in clinical phenotypes, pathological features and genetic heredities, and it is still unclear whether CHCHD2 variants could explain these three diseases. The present study screened all exons of the CHCHD2 gene in a total of 780 patients (511 AD, 181 ALS and 88 FTD) and 500 healthy controls from the Chinese Han population...
May 3, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29747023/assessment-of-dna-repair-susceptibility-genes-identified-by-whole-exome-sequencing-in-head-and-neck-cancer
#7
Raima Das, Sharbadeb Kundu, Shaheen Laskar, Yashmin Choudhury, Sankar Kumar Ghosh
Head and neck cancer (HNC), the sixth most common cancer globally, stands second in India. In Northeast (NE) India, it is the sixth most common cause of death in males and seventh in females. Prolonged tobacco and alcohol consumption constitute the major etiological factors for HNC development, which induce DNA damage. Therefore, DNA repair pathway is a crucial system in maintaining genomic integrity and preventing carcinogenesis. The present work was aimed to predict the consequence of significant germline variants of the DNA repair genes in disease predisposition...
April 26, 2018: DNA Repair
https://www.readbyqxmd.com/read/29727914/germline-mutations-in-dna-repair-genes-are-associated-with-bladder-cancer-risk-and-unfavorable-prognosis
#8
Rong Na, Yishuo Wu, Guangliang Jiang, Hongjie Yu, Xiaoling Lin, Meilin Wang, Carly A Conran, Richard J Fantus, Ning Zhang, Shenghua Liu, Brian T Helfand, S Lilly Zheng, William B Isaacs, Qiang Ding, Zhoujun Shen, Jianfeng Xu
OBJECTIVES: Germline DNA repair gene mutations in bladder cancer (BCa) are poorly characterized. We therefore sought to perform a systematic evaluation of whether these mutations are associated with increased risk of BCa and aggressive disease. MATERIALS AND METHODS: Germline DNA from 98 BCa patients was analyzed for 54 DNA repair genes using a customized targeted sequencing panel. Population control data were obtained from the public databases Exome Aggregation Consortium database (ExAC) and Genome Aggregation Database (gnomAD)...
May 4, 2018: BJU International
https://www.readbyqxmd.com/read/29726057/mutations-and-common-variants-in-the-human-arginase-1-arg1-gene-impact-on-patients-diagnostic-and-protein-structure-considerations
#9
Carmen Diez-Fernandez, Véronique Rüfenacht, Corinne Gemperle, Ralph Fingerhut, Johannes Häberle
The urea cycle disorder argininemia is caused by a defective arginase 1 (ARG1) enzyme resulting from mutations in the ARG1 gene. Patients generally develop hyperargininemia, spastic paraparesis, progressive neurological and intellectual impairment and persistent growth retardation. Interestingly, in contrast to other urea cycle disorders, hyperammonemia is rare. We report here 66 mutations (12 of which are novel), including 30 missense mutations, 7 nonsense, 10 splicing, 15 deletions, two duplications, one small insertion and one translation initiation codon mutation...
May 3, 2018: Human Mutation
https://www.readbyqxmd.com/read/29723276/entprise-x-predicting-disease-associated-frameshift-and-nonsense-mutations
#10
Hongyi Zhou, Mu Gao, Jeffrey Skolnick
To exploit the plethora of information provided by Next Generation Sequencing, the identification of the genetic mutations responsible for disease in general or cancer in particular, among the thousands of neutral germline or somatic variations is a crucial task. Genome-wide association studies for the detection of disease-associated genes or cancer drivers can only identify common variations or driver genes in a cohort of patients. Thus, they cannot discover unique disease-associated mutations or cancer driver genes on a personal basis...
2018: PloS One
https://www.readbyqxmd.com/read/29721912/a-middle-eastern-founder-mutation-expands-the-genotypic-and-phenotypic-spectrum-of-mitochondrial-micu1-deficiency-a-report-of-13-patients
#11
Sara Musa, Wafaa Eyaid, Kimberli Kamer, Rehab Ali, Mariam Al-Mureikhi, Noora Shahbeck, Fatma Al Mesaifri, Nawal Makhseed, Zakkiriah Mohamed, Wafaa Ali AlShehhi, Vamsi K Mootha, Jane Juusola, Tawfeg Ben-Omran
MICU1 encodes a Ca2+ sensing, regulatory subunit of the mitochondrial uniporter, a selective calcium channel within the organelle's inner membrane. Ca2+ entry into mitochondria helps to buffer cytosolic Ca2+ transients and also activates ATP production within the organelle. Mutations in MICU1 have previously been reported in 17 children from nine families with muscle weakness, fatigue, normal lactate, and persistently elevated creatine kinase, as well as variable features that include progressive extrapyramidal signs, learning disabilities, nystagmus, and cataracts...
May 3, 2018: JIMD Reports
https://www.readbyqxmd.com/read/29692759/report-of-a-novel-shox-missense-variant-in-a-boy-with-short-stature-and-his-mother-with-leri-weill-dyschondrosteosis
#12
Laura Lucchetti, Paolo Prontera, Amedea Mencarelli, Ester Sallicandro, Annalisa Mencarelli, Marta Cofini, Alberto Leonardi, Gabriela Stangoni, Laura Penta, Susanna Esposito
Heterozygous mutations in the SHOX gene or in the upstream and downstream enhancer elements are associated with 2-22% of cases of idiopathic short stature (OMIM #300582) and with 60% of cases of Leri-Weill dyschondrosteosis (OMIM #127300) with which female subjects are generally more severely affected. Approximately 80-90% of SHOX pathogenic variants are deletions or duplications, and the remaining 10-20% are point mutations that primarily give rise to missense variants. The clinical interpretation of novel variants, particularly missense variants, can be challenging and can remain of uncertain significance...
2018: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29692703/pleiotropic-effects-of-variants-in-dementia-genes-in-parkinson-disease
#13
Laura Ibanez, Umber Dube, Albert A Davis, Maria V Fernandez, John Budde, Breanna Cooper, Monica Diez-Fairen, Sara Ortega-Cubero, Pau Pastor, Joel S Perlmutter, Carlos Cruchaga, Bruno A Benitez
Background: The prevalence of dementia in Parkinson disease (PD) increases dramatically with advancing age, approaching 80% in patients who survive 20 years with the disease. Increasing evidence suggests clinical, pathological and genetic overlap between Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia with PD. However, the contribution of the dementia-causing genes to PD risk, cognitive impairment and dementia in PD is not fully established. Objective: To assess the contribution of coding variants in Mendelian dementia-causing genes on the risk of developing PD and the effect on cognitive performance of PD patients...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29689380/mpa-a-free-accessible-and-efficient-pipeline-for-single-nucleotide-variant-annotation-and-prioritization-for-next-generation-sequencing-routine-molecular-diagnosis
#14
Kevin Yauy, David Baux, Henri Pegeot, Charles Van Goethem, Charly Mathieu, Thomas Guignard, Raul Juntas Morales, Delphine Lacourt, Martin Krahn, Vilma-Lotta Lehtokari, Gisele Bonne, Sylvie Tuffery-Giraud, Michel Koenig, Mireille Cossée
Interpretation of next-generation sequencing data constitutes the main limitation in molecular genetics diagnosis. In diagnosis of myopathies and muscular dystrophies (MMD), another major issue is to efficiently predict pathogenicity of variants identified in large genes, especially TTN, since current in silico prediction tools show limitations to predict and rank the numerous variants of such genes. We propose a unique variant prioritization score called mobidic prioritization algorithm (MPA) based on curated interpretation for previously reported variants, biological assumptions, and splice and missense predictors to prioritize all types of single nucleotide variants...
April 21, 2018: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/29658329/identification-of-a-novel-mutation-in-fgfr1-gene-in-patients-with-kallmann-syndrome-by-high-throughput-sequencing
#15
Bao-Fang Jin, Zhi-Yong Ji, Zhi-Ying Su, Li-Bin Mei, Xian-Jing Huang, Shao-Bin Lin, Ping Li, Yan-Wei Sha
Kallmann syndrome (KS) is a rare clinical and genetic heterogeneity disease, which is familial or sporadic. KS is known to have three patterns of inheritance: X linked recessive inheritance, autosomal dominant inheritance and rare autosomal recessive inheritance. Here, we report a sibling pedigree with autosomal dominant inheritance of KS, and we identified a novel heterozygous frameshift mutation c.299_300insCCGCAGACTCCGGCCTCTATGC (p.C101Rfs*17) in FGFR1 gene using whole-exome sequencing (WES). The mutation and affection status were cosegregated...
April 15, 2018: Systems Biology in Reproductive Medicine
https://www.readbyqxmd.com/read/29644397/coq2-variants-in-parkinson-s-disease-and-multiple-system-atrophy
#16
Michitaka Mikasa, Kazuaki Kanai, Yuanzhe Li, Hiroyo Yoshino, Kaoru Mogushi, Arisa Hayashida, Aya Ikeda, Sumihiro Kawajiri, Yasuyuki Okuma, Kenichi Kashihara, Tatsuya Sato, Hiroshi Kondo, Manabu Funayama, Kenya Nishioka, Nobutaka Hattori
Coenzyme Q2, polyprenyltransferase (COQ2) variants have been reported to be associated with multiple system atrophy (MSA). However, the relationship between COQ2 variants and familial Parkinson's disease (PD) remains unclear. We investigated the frequency of COQ2 variants and clinical symptoms among familial PD and MSA. We screened COQ2 using the Sanger method in 123 patients with familial PD, 52 patients with sporadic PD, and 39 patients with clinically diagnosed MSA. Clinical information was collected from medical records for the patients with COQ2 variants...
April 11, 2018: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29618362/genetic-analysis-of-wnt-pcp-genes-in-neural-tube-defects
#17
Zhongzhong Chen, Yunping Lei, Xuanye Cao, Yufang Zheng, Fang Wang, Yihua Bao, Rui Peng, Richard H Finnell, Ting Zhang, Hongyan Wang
BACKGROUND: Mouse homozygous mutants in Wnt/planar cell polarity (PCP) pathway genes have been shown to cause neural tube defects (NTDs) through the disruption of normal morphogenetic processes critical to neural tube closure (NTC). Knockout mice that are heterozygotes of single PCP genes likely fail to produce NTD phenotypes, yet damaging variants detected in human NTDs are almost always heterozygous, suggesting that other deleterious interacting variants are likely to be present. Nonetheless, the Wnt/PCP pathway remains a genetic hotspot...
April 4, 2018: BMC Medical Genomics
https://www.readbyqxmd.com/read/29593342/genetic-variants-and-pathways-implicated-in-a-pediatric-inflammatory-bowel-disease-cohort
#18
Kelly A Shaw, David J Cutler, David Okou, Anne Dodd, Bruce J Aronow, Yael Haberman, Christine Stevens, Thomas D Walters, Anne Griffiths, Robert N Baldassano, Joshua D Noe, Jeffrey S Hyams, Wallace V Crandall, Barbara S Kirschner, Melvin B Heyman, Scott Snapper, Stephen Guthery, Marla C Dubinsky, Jason M Shapiro, Anthony R Otley, Mark Daly, Lee A Denson, Subra Kugathasan, Michael E Zwick
In the United States, approximately 5% of individuals with inflammatory bowel disease (IBD) are younger than 20 years old. Studies of pediatric cohorts can provide unique insights into genetic architecture of IBD, which includes Crohn's disease (CD) and ulcerative colitis (UC). Large genome-wide association studies have found more than 200 IBD-associated loci but explain a minority of disease variance for CD and UC. We sought to characterize the contribution of rare variants to disease development, comparing exome sequencing of 368 pediatric IBD patients to publicly available exome sequencing (dbGaP) and aggregate frequency data (ExAC)...
March 28, 2018: Genes and Immunity
https://www.readbyqxmd.com/read/29590403/p-val804met-the-most-frequent-pathogenic-mutation-in-ret-confers-a-very-low-lifetime-risk-of-medullary-thyroid-cancer
#19
Chey Loveday, Katherine Josephs, Daniel Chubb, Adam Gunning, Louise Izatt, Marc Tischkovitz, Sian Ellard, Clare Turnbull
Context: To date, penetrance figures for medullary thyroid cancer (MTC) for variants in RET have been estimated from families ascertained on account of presence of MTC. Objective: To gain estimates of penetrance unbiased by ascertainment, we analyzed 61 RET mutations assigned as disease-causing by the ATA in population whole exome sequencing data. Design: For the 61 RET mutations, we used analyses of the observed allele frequencies in ∼51,000 individuals from non-TCGA ExAC, assuming lifetime penetrance for MTC of 90%, 50% and unbounded...
March 23, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29590294/leveraging-known-genomic-variants-to-improve-detection-of-variants-especially-close-by-indels
#20
Nam S Vo, Vinhthuy Phan
Motivation: The detection of genomic variants has great significance in genomics, bioinformatics and biomedical research and applications. However, despite a lot of effort, Indels and structural variants are still under-characterized compared to SNPs. Current approaches based on next-generation sequencing data usually require large numbers of reads (high coverage) to be able to detect such types of variants accurately. However Indels, especially those close to each other, are still hard to detect accurately...
March 24, 2018: Bioinformatics
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