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https://www.readbyqxmd.com/read/29334895/challenges-imposed-by-minor-reference-alleles-on-the-identification-and-reporting-of-clinical-variants-from-exome-data
#1
Mahmoud Koko, Mohammed O E Abdallah, Mutaz Amin, Muntaser Ibrahim
BACKGROUND: The conventional variant calling of pathogenic alleles in exome and genome sequencing requires the presence of the non-pathogenic alleles as genome references. This hinders the correct identification of variants with minor and/or pathogenic reference alleles warranting additional approaches for variant calling. RESULTS: More than 26,000 Exome Aggregation Consortium (ExAC) variants have a minor reference allele including variants with known ClinVar disease alleles...
January 15, 2018: BMC Genomics
https://www.readbyqxmd.com/read/29330013/a-functional-splicing-variant-associated-with-decreased-asthma-risk-abolishes-the-ability-of-gasdermin-b-gsmdb-to-induce-epithelial-cell-pyroptosis
#2
Ronald A Panganiban, Maoyun Sun, Amber Dahlin, Hae-Ryung Park, Mengyuan Kan, Blanca E Himes, Jennifer A Mitchel, Carlos Iribarren, Eric Jorgenson, Scott H Randell, Elliot Israel, Kelan Tantisira, Stephanie Shore, Jin-Ah Park, Scott T Weiss, Ann Chen Wu, Quan Lu
BACKGROUND: Genetic variants in the chromosomal region 17q21 are consistently associated with asthma. However, mechanistic studies have not yet linked any of the associated variants to a function that could influence asthma, and as a result, the identity of the asthma gene(s) remains elusive. OBJECTIVES: We sought to identify and characterize functional variants in the 17q21 locus. METHODS: We used the Exome Aggregation Consortium (ExAC) browser to identify coding (amino acid-changing) variants in the 17q21 locus...
January 9, 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29325022/large-scale-exome-datasets-reveal-a-new-class-of-adaptor-related-protein-complex-2-sigma-subunit-ap2%C3%AF-mutations-located-at-the-interface-with-the-ap2-alpha-subunit-that-impair-calcium-sensing-receptor-signalling
#3
Caroline M Gorvin, Raghu Metpally, Victoria J Stokes, Fadil M Hannan, Sarath B Krishnamurthy, John D Overton, Jeffrey G Reid, Gerda E Breitwieser, Rajesh V Thakker
Mutations of the sigma subunit of the heterotetrameric adaptor-related protein complex 2 (AP2σ) impair signalling of the calcium-sensing receptor (CaSR), and cause familial hypocalciuric hypercalcaemia type 3 (FHH3). To date, FHH3-associated AP2σ mutations have only been identified at one residue, Arg15. We hypothesized that additional rare AP2σ variants may also be associated with altered CaSR function and hypercalcaemia, and sought for these by analysing >111,995 exomes (>60,706 from ExAc and dbSNP, and 51,289 from the Geisinger Health System-Regeneron DiscovEHR dataset which also contains clinical data)...
January 9, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29320387/identification-of-inherited-retinal-disease-associated-genetic-variants-in-11-candidate-genes
#4
Galuh D N Astuti, L Ingeborgh van den Born, M Imran Khan, Christian P Hamel, Béatrice Bocquet, Gaël Manes, Mathieu Quinodoz, Manir Ali, Carmel Toomes, Martin McKibbin, Mohammed E El-Asrag, Lonneke Haer-Wigman, Chris F Inglehearn, Graeme C M Black, Carel B Hoyng, Frans P M Cremers, Susanne Roosing
Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is challenging. In this study, we searched for novel candidate IRD gene-associated variants in isolated IRD families, assessed their causality, and searched for novel genotype-phenotype correlations. Whole exome sequencing was performed in 11 probands affected with IRDs...
January 10, 2018: Genes
https://www.readbyqxmd.com/read/29300972/a-recurrent-de-novo-missense-mutation-in-ubtf-causes-developmental-neuroregression
#5
Camilo Toro, Roderick T Hori, May Christine V Malicdan, Cynthia J Tifft, Amy Goldstein, William A Gahl, David R Adams, Fauni Harper, Lynne A Wolfe, Jianfeng Xiao, Mohammad M Khan, Jun Tian, Kevin A Hope, Lawrence T Reiter, Michel G Tremblay, Thomas Moss, Alexis L Franks, Chris Balak, Mark S LeDoux
UBTF (upstream binding transcription factor) exists as two isoforms; UBTF1 regulates rRNA transcription by RNA polymerase 1, whereas UBTF2 regulates mRNA transcription by RNA polymerase 2. Herein, we describe 4 patients with very similar patterns of neuroregression due to recurrent de novo mutations in UBTF (GRCh37/hg19, NC_000017.10:g.42290219C>T, NM_014233.3:c.628G>A) resulting in the same amino acid change in both UBTF1 and UBTF2 (p.Glu210Lys [p.E210K]). Disease onset in our cohort was at 2.5 to 3 yrs and characterized by slow progression of global motor, cognitive and behavioral dysfunction...
January 2, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29273096/genetic-variation-in-human-drug-related-genes
#6
Charlotta Pauline Irmgard Schärfe, Roman Tremmel, Matthias Schwab, Oliver Kohlbacher, Debora Susan Marks
BACKGROUND: Variability in drug efficacy and adverse effects are observed in clinical practice. While the extent of genetic variability in classic pharmacokinetic genes is rather well understood, the role of genetic variation in drug targets is typically less studied. METHODS: Based on 60,706 human exomes from the ExAC dataset, we performed an in-depth computational analysis of the prevalence of functional variants in 806 drug-related genes, including 628 known drug targets...
December 22, 2017: Genome Medicine
https://www.readbyqxmd.com/read/29261847/tsc1-mutations-in-keratoconus-patients-with-or-without-tuberous-sclerosis
#7
Yelena Bykhovskaya, Majid Fardaei, Mariam Lotfy Khaled, Mahmood Nejabat, Ramin Salouti, Hassan Dastsooz, Yutao Liu, Soroor Inaloo, Yaron S Rabinowitz
Purpose: To test candidate genes TSC1 and TSC2 in a family affected by tuberous sclerosis complex (TSC) where proband was also diagnosed with bilateral keratoconus (KC) and to test the hypothesis that defects in the same gene may lead to a nonsyndromic KC. Methods: Next-generation sequencing of TSC1 and TSC2 genes was performed in a proband affected by TSC and KC. Identified mutation was confirmed by Sanger DNA sequencing. Whole exome sequencing (WES) was performed in patients with nonsyndromic KC...
December 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29242557/the-metabolic-syndrome-associated-small-g-protein-arl15-plays-a-role-in-adipocyte-differentiation-and-adiponectin-secretion
#8
Nuno Rocha, Felicity Payne, Isabel Huang-Doran, Alison Sleigh, Katherine Fawcett, Claire Adams, Anna Stears, Vladimir Saudek, Stephen O'Rahilly, Inês Barroso, Robert K Semple
Common genetic variants at the ARL15 locus are associated with plasma adiponectin, insulin and HDL cholesterol concentrations, obesity, and coronary atherosclerosis. The ARL15 gene encodes a small GTP-binding protein whose function is currently unknown. In this study adipocyte-autonomous roles for ARL15 were investigated using conditional knockdown of Arl15 in murine 3T3-L1 (pre)adipocytes. Arl15 knockdown in differentiated adipocytes impaired adiponectin secretion but not adipsin secretion or insulin action, while in preadipocytes it impaired adipogenesis...
December 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29237690/analysis-of-60%C3%A2-706-exomes-questions-the-role-of-de-novo-variants-previously-implicated-in-cardiac-disease
#9
Christian Paludan-Müller, Gustav Ahlberg, Jonas Ghouse, Jesper H Svendsen, Stig Haunsø, Morten S Olesen
BACKGROUND: De novo variants in the exome occur at a rate of 1 per individual per generation, and because of the low reproductive fitness for de novo variants causing severe disease, the likelihood of finding these as standing variations in the general population is low. Therefore, this study sought to evaluate the pathogenicity of de novo variants previously associated with cardiac disease based on a large population-representative exome database. METHODS AND RESULTS: We performed a literature search for previous publications on de novo variants associated with severe arrhythmias and structural heart diseases and investigated whether these variants were present in the Exome Aggregation Consortium (ExAC) database (n=60 706)...
December 2017: Circulation. Cardiovascular Genetics
https://www.readbyqxmd.com/read/29226631/novel-compound-heterozygous-mutations-in-gpt2-linked-to-microcephaly-and-intellectual-developmental-disability-with-or-without-spastic-paraplegia
#10
Hande Kaymakcalan, Yanki Yarman, Nukte Goc, Fatih Toy, Cihan Meral, A Gulhan Ercan-Sencicek, Murat Gunel
We here describe novel compound heterozygous missense variants, NM_133443:c.[400C>T] and NM_133443:[1435G>A], in the glutamic-pyruvic transaminase 2 (GPT2) gene in a large consanguineous family with two affected siblings diagnosed with microcephaly intellectual disability and developmental delay (IDD). In addition to these clinical phenotypes, the male sibling has spastic paraplegia, and the female sibling has epilepsy. Their four extended family members have IDD and microcephaly. Both of these variants, c...
December 11, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29208948/a-novel-mutation-in-slc1a3-causes-episodic-ataxia
#11
Kazuhiro Iwama, Aya Iwata, Masaaki Shiina, Satomi Mitsuhashi, Satoko Miyatake, Atsushi Takata, Noriko Miyake, Kazuhiro Ogata, Shuichi Ito, Takeshi Mizuguchi, Naomichi Matsumoto
Episodic ataxias (EAs) are rare channelopathies characterized by recurrent ataxia and vertigo, having eight subtypes. Mutated genes were found in four of these eight subtypes (EA1, EA2, EA5, and EA6). To date, only four missense mutations in the Solute Carrier Family 1 Member 3 gene (SLC1A3) have been reported to cause EA6. SLC1A3 encodes excitatory amino-acid transporter 1, which is a trimeric transmembrane protein responsible for glutamate transport in the synaptic cleft. In this study, we found a novel missense mutation, c...
December 5, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/29198386/x-linked-glomerulopathy-due-to-col4a5-founder%C3%A2-variant
#12
Moumita Barua, Rohan John, Lorenzo Stella, Weili Li, Nicole M Roslin, Bedra Sharif, Saidah Hack, Ginette Lajoie-Starkell, Andrew L Schwaderer, Brian Becknell, Matthias Wuttke, Anna Köttgen, Daniel Cattran, Andrew D Paterson, York Pei
Alport syndrome is a rare hereditary disorder caused by rare variants in 1 of 3 genes encoding for type IV collagen. Rare variants in COL4A5 on chromosome Xq22 cause X-linked Alport syndrome, which accounts for ∼80% of the cases. Alport syndrome has a variable clinical presentation, including progressive kidney failure, hearing loss, and ocular defects. Exome sequencing performed in 2 affected related males with an undefined X-linked glomerulopathy characterized by global and segmental glomerulosclerosis, mesangial hypercellularity, and vague basement membrane immune complex deposition revealed a COL4A5 sequence variant, a substitution of a thymine by a guanine at nucleotide 665 (c...
November 29, 2017: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
https://www.readbyqxmd.com/read/29197136/properties-of-human-genes-guided-by-their-enrichment-in-rare-and-common-variants
#13
Eman Alhuzimi, Luis G Leal, Michael J E Sternberg, Alessia David
We analysed of 563,099 common (minor allele frequency, MAF≥0.01) and rare (MAF < 0.01) genetic variants annotated in ExAC and UniProt and 26,884 disease-causing variants from ClinVar and UniProt occurring in the coding region of 17,975 human protein-coding genes. Three novel sets of genes were identified: those enriched in rare variants (n = 32 genes), in common variants (n = 282 genes) and in disease-causing variants (n = 800 genes). Genes enriched in rare variants have far greater similarities in terms of biological and network properties to genes enriched in disease-causing variants, than to genes enriched in common variants...
December 2, 2017: Human Mutation
https://www.readbyqxmd.com/read/29163635/departure-from-hardy-weinberg-equilibrium-and-genotyping-error
#14
Bowang Chen, John W Cole, Caspar Grond-Ginsbach
Objective: Departure from Hardy Weinberg Equilibrium (HWE) may occur due to a variety of causes, including purifying selection, inbreeding, population substructure, copy number variation or genotyping error. We searched for specific characteristics of HWE-departure due to genotyping error. Methods: Genotypes of a random set of genetic variants were obtained from the Exome Aggregation Consortium (ExAC) database. Variants with <80% successful genotypes or with minor allele frequency (MAF) <1% were excluded...
2017: Frontiers in Genetics
https://www.readbyqxmd.com/read/29155419/catching-hidden-variation-systematic-correction-of-reference-minor-allele-annotation-in-clinical-variant-calling
#15
Yury A Barbitoff, Igor V Bezdvornykh, Dmitrii E Polev, Elena A Serebryakova, Andrey S Glotov, Oleg S Glotov, Alexander V Predeus
PurposeWe comprehensively assessed the influence of reference minor alleles (RMAs), one of the inherent problems of the human reference genome sequence.MethodsThe variant call format (VCF) files provided by the 1000 Genomes and Exome Aggregation Consortium (ExAC) consortia were used to identify RMA sites. All coding RMA sites were checked for concordance with UniProt and the presence of same codon variants. RMA-corrected predictions of functional effect were obtained with SIFT, PolyPhen-2, and PROVEAN standalone tools and compared with dbNSFP v2...
October 26, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/29141314/-a-novel-compound-heterozygous-mutation-in-abca3-gene-in-a-child-with-diffuse-parenchymal-lung-disease
#16
Y M Bao, X L Liu, X L Liu, J H Chen, Y J Zheng
Objective: To summarize the clinical characteristics of the diffuse parenchymal lung diseases in a child caused by a novel compound heterozygous ABCA3 mutation and explore the association between the phenotype and ABCA3 mutation. Method: The clinical material of a patient diagnosed with diffuse parenchymal lung disease with ABCA3 mutation in December 2016 in Shenzhen Children's Hospital was analyzed. The information about ABCA3 gene mutation updated before April, 2017 was searched and collected from the gene databases (including 1000Genomes, HGMD, EXAC) and the literatures (including Wanfang Chinese database and Pubmed)...
November 2, 2017: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
https://www.readbyqxmd.com/read/29101506/estimated-prevalence-of-potentially-damaging-variants-in-the-leptin-gene
#17
Adriana Nunziata, Guntram Borck, Jan-Bernd Funcke, Katja Kohlsdorf, Stephanie Brandt, Anke Hinney, Barbara Moepps, Peter Gierschik, Klaus-Michael Debatin, Pamela Fischer-Posovszky, Martin Wabitsch
BACKGROUND: Mutations in the leptin gene (LEP) can alter the secretion or interaction of leptin with its receptor, leading to extreme early-onset obesity. The purpose of this work was to estimate the prevalence of heterozygous and homozygous mutations in the leptin gene with the help of the Exome Aggregation Consortium (ExAC) database ( http://exac.broadinstitute.org/about ). RESULTS: The ExAC database encompasses exome sequencing data from 60,706 individuals. We searched for listed leptin variants and identified 36 missense, 1 in-frame deletion, and 3 loss-of-function variants...
November 3, 2017: Molecular and Cellular Pediatrics
https://www.readbyqxmd.com/read/29091718/analysis-of-neurodegenerative-mendelian-genes-in-clinically-diagnosed-alzheimer-disease
#18
Maria Victoria Fernández, Jong Hun Kim, John P Budde, Kathleen Black, Alexandra Medvedeva, Ben Saef, Yuetiva Deming, Jorge Del-Aguila, Laura Ibañez, Umber Dube, Oscar Harari, Joanne Norton, Rachel Chasse, John C Morris, Alison Goate, Carlos Cruchaga
Alzheimer disease (AD), Frontotemporal lobar degeneration (FTD), Amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD) have a certain degree of clinical, pathological and molecular overlap. Previous studies indicate that causative mutations in AD and FTD/ALS genes can be found in clinical familial AD. We examined the presence of causative and low frequency coding variants in the AD, FTD, ALS and PD Mendelian genes, in over 450 families with clinical history of AD and over 11,710 sporadic cases and cognitive normal participants from North America...
November 2017: PLoS Genetics
https://www.readbyqxmd.com/read/29080873/-a-bioinformatic-pipeline-for-ngs-data-analysis-and-mutation-calling-in-human-solid-tumors
#19
K Yu Tsukanov, A Yu Krasnenko, D A Plakhina, D O Korostin, A V Churov, O S Druzhilovskaya, D V Rebrikov, V V Ilinsky
We aimed to develop a pipeline for the bioinformatic analysis and interpretation of NGS data and detection of a wide range of single-nucleotide somatic mutations within tumor DNA. Initially, the NGS reads were submitted to a quality control check by the Cutadapt program. Low-quality 3¢-nucleotides were removed. After that the reads were mapped to the reference genome hg19 (GRCh37.p13) by BWA. The SAMtools program was used for exclusion of duplicates. MuTect was used for SNV calling. The functional effect of SNVs was evaluated using the algorithm, including annotation and evaluation of SNV pathogenicity by SnpEff and analysis of such databases as COSMIC, dbNSFP, Clinvar, and OMIM...
October 2017: Biomedit︠s︡inskai︠a︡ Khimii︠a︡
https://www.readbyqxmd.com/read/29079751/a-missense-mutation-in-slc26a3-is-associated-with-human-male-subfertility-and-impaired-activation-of-cftr
#20
Satu Wedenoja, Ahlam Khamaysi, Liana Shimshilashvili, Shireen Anbtawe-Jomaa, Outi Elomaa, Jorma Toppari, Pia Höglund, Kristiina Aittomäki, Christer Holmberg, Outi Hovatta, Juha S Tapanainen, Ehud Ohana, Juha Kere
Chloride absorption and bicarbonate excretion through exchange by the solute carrier family 26 member 3 (SLC26A3) and cystic fibrosis transmembrane conductance regulator (CFTR) are crucial for many tissues including sperm and epithelia of the male reproductive tract. Homozygous SLC26A3 mutations cause congenital chloride diarrhea with male subfertility, while homozygous CFTR mutations cause cystic fibrosis with male infertility. Some homozygous or heterozygous CFTR mutations only manifest as male infertility...
October 27, 2017: Scientific Reports
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