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https://www.readbyqxmd.com/read/27899644/the-dbgap-data-browser-a-new-tool-for-browsing-dbgap-controlled-access-genomic-data
#1
Kira M Wong, Kristofor Langlais, Geoffrey S Tobias, Colette Fletcher-Hoppe, Donna Krasnewich, Hilary S Leeds, Laura Lyman Rodriguez, Georgy Godynskiy, Valerie A Schneider, Erin M Ramos, Stephen T Sherry
The database of Genotypes and Phenotypes (dbGaP) Data Browser (https://www.ncbi.nlm.nih.gov/gap/ddb/) was developed in response to requests from the scientific community for a resource that enable view-only access to summary-level information and individual-level genotype and sequence data associated with phenotypic features maintained in the controlled-access tier of dbGaP. Until now, the dbGaP controlled-access environment required investigators to submit a data access request, wait for Data Access Committee review, download each data set and locally examine them for potentially relevant information...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27899611/the-exac-browser-displaying-reference-data-information-from-over-60-000-exomes
#2
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
#3
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/27896284/analyses-of-more-than-60-000-exomes-questions-the-role-of-numerous-genes-previously-associated-with-dilated-cardiomyopathy
#4
Nina Nouhravesh, Gustav Ahlberg, Jonas Ghouse, Charlotte Andreasen, Jesper H Svendsen, Stig Haunsø, Henning Bundgaard, Peter E Weeke, Morten S Olesen
BACKGROUND: Hundreds of genetic variants have been described as disease causing in dilated cardiomyopathy (DCM). Some of these associations are now being questioned. We aimed to identify the prevalence of previously DCM associated variants in the Exome Aggregation Consortium (ExAC), in order to identify potentially false-positive DCM variants. METHODS: Variants listed as DCM disease-causing variants in the Human Gene Mutation Database were extracted from ExAC. Pathogenicity predictions for these variants were mined from dbNSFP v 2...
November 2016: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/27895300/thsd1-thrombospondin-type-1-domain-containing-protein-1-mutation-in-the-pathogenesis-of-intracranial-aneurysm-and-subarachnoid-hemorrhage
#5
Teresa Santiago-Sim, Xiaoqian Fang, Morgan L Hennessy, Stephen V Nalbach, Steven R DePalma, Ming Sum Lee, Steven C Greenway, Barbara McDonough, Georgene W Hergenroeder, Kyla J Patek, Sarah M Colosimo, Krista J Qualmann, John P Hagan, Dianna M Milewicz, Calum A MacRae, Susan M Dymecki, Christine E Seidman, J G Seidman, Dong H Kim
BACKGROUND AND PURPOSE: A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage. This study seeks to define a specific gene whose mutation leads to disease. METHODS: More than 500 IA probands and 100 affected families were enrolled and clinically characterized. Whole exome sequencing was performed on a large family, revealing a segregating THSD1 (thrombospondin type 1 domain containing protein 1) mutation. THSD1 was sequenced in other probands and controls...
December 2016: Stroke; a Journal of Cerebral Circulation
https://www.readbyqxmd.com/read/27886675/pathogenic-germline-mcm9-variants-are-rare-in-australian-lynch-like-syndrome-patients
#6
Qing Liu, Luke B Hesson, Andrea C Nunez, Deborah Packham, Nicholas J Hawkins, Robyn L Ward, Mathew A Sloane
Lynch syndrome is a hereditary cancer syndrome caused by the autosomal dominant inheritance of loss-of-function mutations in DNA mismatch repair (MMR) genes. Approximately one quarter of clinically suspected cases have no identifiable germline mutation in any MMR gene, a condition known as Lynch-like syndrome (LLS). MCM9 was recently identified as the DNA helicase in the mammalian MMR complex and loss of helicase activity results in microsatellite instability. We hypothesized that pathogenic variants in MCM9 may account for LLS...
November 2016: Cancer Genetics
https://www.readbyqxmd.com/read/27884173/revisiting-the-morbid-genome-of-mendelian-disorders
#7
Mohamed Abouelhoda, Tariq Faquih, Mohamed El-Kalioby, Fowzan S Alkuraya
BACKGROUND: The pathogenicity of many Mendelian variants has been challenged by large-scale sequencing efforts. However, many rare and benign "disease mutations" are difficult to analyze due to their rarity. The Saudi Arabian variome is enriched for homozygosity due to inbreeding, a key advantage that can be exploited for the critical examination of previously published variants. RESULTS: We collated all "disease-related mutations" listed in the Human Gene Mutation Database (HGMD) and ClinVar, including "variants of uncertain significance" (VOUS)...
November 24, 2016: Genome Biology
https://www.readbyqxmd.com/read/27855150/a-novel-missense-mutation-in-the-transcription-factor-foxf1-co-segregating-with-infantile-hypertrophic-pyloric-stenosis-in-the-extended-pedigree-linked-to-ihps5-on-chromosome-16q24
#8
Kate V Everett, Paris Ataliotis, Barry A Chioza, Charles Shaw-Smith, Eddie Mk Chung
BACKGROUND: The aim was to identify susceptibility alleles for infantile hypertrophic pyloric stenosis (IHPS) in a pedigree previously linked to IHPS5 on chromosome 16q24. METHODS: We screened the positional and functional candidate gene FOXF1 by Sanger sequencing in a single affected individual. All family members for whom DNA was available were genotyped to determine co-segregation status of the putative causal variant. Immunofluorescence studies were performed to compare the cellular localisation of wildtype and mutant form of the protein...
November 17, 2016: Pediatric Research
https://www.readbyqxmd.com/read/27844030/archetypal-notch3-mutations-frequent-in-public-exome-implications-for-cadasil
#9
Julie W Rutten, Hans G Dauwerse, Gido Gravesteijn, Martine J van Belzen, Jeroen van der Grond, James M Polke, Manuel Bernal-Quiros, Saskia A J Lesnik Oberstein
OBJECTIVE: To determine the frequency of distinctive EGFr cysteine altering NOTCH3 mutations in the 60,706 exomes of the exome aggregation consortium (ExAC) database. METHODS: ExAC was queried for mutations distinctive for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), namely mutations leading to a cysteine amino acid change in one of the 34 EGFr domains of NOTCH3. The genotype-phenotype correlation predicted by the ExAC data was tested in an independent cohort of Dutch CADASIL patients using quantified MRI lesions...
November 2016: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/27835862/a-novel-mutation-in-nuclear-prelamin-a-recognition-factor-like-causes-diffuse-pulmonary-arteriovenous-malformations
#10
Hong-Zhou Liu, Chun-Xian Du, Jing Luo, Xue-Ping Qiu, Zu-Hua Li, Qi-Yong Lou, Zhan Yin, Fang Zheng
Two daughters in a Chinese consanguineous family were diagnosed as diffuse pulmonary arteriovenous malformations (PAVMs) and screened using whole exome sequencing (WES) and copy number variations (CNVs) chips. Though no mutation was found in the established causative genes of capillary malformation-AVMs (CM-AVMs) or PAVMs, Ser161Ile (hg19 NM_022493 c.482G>T) mutation in nuclear prelamin A recognition factor-like (NARFL) was identified. Ser161Ile mutation in NARFL conservation region was predicted to be deleterious and absent in 500 population controls and Exome Aggregation Consortium (ExAC) Database...
November 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27799474/mirdnmr-a-gene-centered-database-of-background-de-novo-mutation-rates-in-human
#11
Yi Jiang, Zhongshan Li, Zhenwei Liu, Denghui Chen, Wanying Wu, Yaoqiang Du, Liying Ji, Zi-Bing Jin, Wei Li, Jinyu Wu
De novo germline mutations (DNMs) are the rarest genetic variants proven to cause a considerable number of sporadic genetic diseases, such as autism spectrum disorders, epileptic encephalopathy, schizophrenia, congenital heart disease, type 1 diabetes, and hearing loss. However, it is difficult to accurately assess the cause of DNMs and identify disease-causing genes from the considerable number of DNMs in probands. A common method to this problem is to identify genes that harbor significantly more DNMs than expected by chance, with accurate background DNM rate (DNMR) required...
October 30, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27785597/exome-sequencing-identifies-a-novel-mutation-in-gja8-associated-with-inherited-cataract-in-a-chinese-family
#12
Mei Ren, Xin Guang Yang, Xiao Jie Dang, Jin An Xiao
BACKGROUND: Congenital cataract is a clinical and genetic heterogeneous group of eye disorders that causes visual impairment and childhood blindness. In this study, a Chinese family with congenital cataract is studied. METHODS: In order to identify the genetic defects which were associated with congenital cataract, a whole-exome sequencing approach is performed to screen for the potential mutation-causing disease. RESULTS: The result revealed a novel heterozygous mutation (c...
October 26, 2016: Graefe's Archive for Clinical and Experimental Ophthalmology
https://www.readbyqxmd.com/read/27764668/publicly-available-data-provide-evidence-against-nr1h3-r415q-causing-multiple-sclerosis
#13
Eric Vallabh Minikel, Daniel G MacArthur
It has recently been reported that an NR1H3 missense variant, R415Q, causes a novel familial form of multiple sclerosis (Wang et al., 2016a). This claim is at odds with publicly available data from the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org). The allele frequency of R415Q is not significantly higher in cases (0.024%-0.049%) than in ExAC population controls (0.031%), whereas if R415Q conferred even 50% lifetime risk of developing MS, it would be hundreds of times more common in cases than in controls...
October 19, 2016: Neuron
https://www.readbyqxmd.com/read/27756091/identification-of-novel-prop1-and-pou1f1-mutations-in-patients-with-combined-pituitary-hormone-deficiency
#14
S Birla, R Khadgawat, V P Jyotsna, V Jain, M K Garg, A S Bhalla, A Sharma
Growth hormone deficiency (GHD) results from variations affecting the production and release of growth hormone (GH) and is of 2 types: isolated growth hormone deficiency (IGHD) and combined pituitary hormone deficiency (CPHD). IGHD results from mutations in GH1 and GHRHR while CPHD is associated with defects in transcription factor genes PROP1, POU1F1, and HESX1. The present study reports on screening of POU1F1, PROP1, and HESX1 in CPHD patients and the novel variations identified. Fifty-one CPHD patients from 49 unrelated families clinically diagnosed on the basis of biochemical and imaging investigations along with 100 controls were enrolled...
October 18, 2016: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
https://www.readbyqxmd.com/read/27647783/wes-wgs-reporting-of-mutations-from-cardiovascular-actionable-genes-in-clinical-practice-a-key-role-for-umd-knowledgebases-in-the-era-of-big-databases
#15
Amélie Pinard, David Salgado, Jean-Pierre Desvignes, Ghadi Rai, Nadine Hanna, Pauline Arnaud, Céline Guien, Maria Martinez, Laurence Faivre, Guillaume Jondeau, Catherine Boileau, Stéphane Zaffran, Christophe Béroud, Gwenaëlle Collod-Béroud
High-throughput next-generation sequencing such as whole-exome and whole-genome sequencing are being rapidly integrated into clinical practice. The use of these techniques leads to the identification of secondary variants for which decisions about the reporting or not to the patient need to be made. The American College of Medical Genetics and Genomics recently published recommendations for the reporting of these variants in clinical practice for 56 "actionable" genes. Among these, seven are involved in Marfan Syndrome And Related Disorders (MSARD) resulting from mutations of the FBN1, TGFBR1 and 2, ACTA2, SMAD3, MYH11 and MYLK genes...
December 2016: Human Mutation
https://www.readbyqxmd.com/read/27629930/genetic-variation-exac-boosts-clinical-variant-interpretation-in-rare-diseases
#16
Orli G Bahcall
No abstract text is available yet for this article.
September 15, 2016: Nature Reviews. Genetics
https://www.readbyqxmd.com/read/27616605/assessing-the-general-population-frequency-of-rare-coding-variants-in-the-ext1-and-ext2-genes-previously-implicated-in-hereditary-multiple-exostoses
#17
Diana L Cousminer, Alexandre Arkader, Benjamin F Voight, Maurizio Pacifici, Struan F A Grant
Hereditary multiple exostoses (HME) is a rare childhood-onset skeletal disease linked to mutations in exostosin glycosyltransferase 1 (EXT1) or 2 (EXT2). Patients are heterozygous for either an EXT1 or EXT2 mutation, and it is widely assumed that exostosis formation and associated defects, such as growth retardation and skeletal deformities, require loss-of-heterozygosity or a second hit in affected cells. However, the relevance and phenotypic impact of many presumed pathogenic EXT variants remain uncertain...
November 2016: Bone
https://www.readbyqxmd.com/read/27553520/analysis-of-large-scale-whole-exome-sequencing-data-to-determine-the-prevalence-of-genetically-distinct-forms-of-neuronal-ceroid-lipofuscinosis
#18
David E Sleat, Erika Gedvilaite, Yeting Zhang, Peter Lobel, Jinchuan Xing
The neuronal ceroid lipofuscinoses (NCLs) are a group of fatal, mostly recessive neurodegenerative lysosomal storage diseases. While clinically similar, they are genetically distinct and result from mutations in at least twelve different genes. Estimates of NCL incidence range from 0.6 to 14 per 100,000 live births but vary widely between populations and are influenced by whether patients are classified based upon clinical or genetic criteria. We investigated mutations in twelve NCL genes in ~61,000 individuals represented in the Exome Aggregation Consortium (ExAC) whole exome sequencing database...
November 30, 2016: Gene
https://www.readbyqxmd.com/read/27538377/integration-of-60-000-exomes-and-acmg-guidelines-question-the-role-of-catecholaminergic-polymorphic-ventricular-tachycardia-associated-variants
#19
C Paludan-Müller, G Ahlberg, J Ghouse, C Herfelt, J H Svendsen, S Haunsø, J K Kanters, M S Olesen
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a highly lethal cardiac arrhythmia disease occurring during exercise or psychological stress. CPVT has an estimated prevalence of 1:10,000 and has mainly been associated with variants in calcium-regulating genes. Identification of potential false-positive pathogenic variants was conducted by searching the Exome Aggregation Consortium (ExAC) database (n = 60,706) for variants reported to be associated with CPVT. The pathogenicity of the interrogated variants was assessed using guidelines from the American College of Medical Genetics and Genomics (ACMG) and in silico prediction tools...
August 19, 2016: Clinical Genetics
https://www.readbyqxmd.com/read/27535533/analysis-of-protein-coding-genetic-variation-in-60-706-humans
#20
Monkol Lek, Konrad J Karczewski, Eric V Minikel, Kaitlin E Samocha, Eric Banks, Timothy Fennell, Anne H O'Donnell-Luria, James S Ware, Andrew J Hill, Beryl B Cummings, Taru Tukiainen, Daniel P Birnbaum, Jack A Kosmicki, Laramie E Duncan, Karol Estrada, Fengmei Zhao, James Zou, Emma Pierce-Hoffman, Joanne Berghout, David N Cooper, Nicole Deflaux, Mark DePristo, Ron Do, Jason Flannick, Menachem Fromer, Laura Gauthier, Jackie Goldstein, Namrata Gupta, Daniel Howrigan, Adam Kiezun, Mitja I Kurki, Ami Levy Moonshine, Pradeep Natarajan, Lorena Orozco, Gina M Peloso, Ryan Poplin, Manuel A Rivas, Valentin Ruano-Rubio, Samuel A Rose, Douglas M Ruderfer, Khalid Shakir, Peter D Stenson, Christine Stevens, Brett P Thomas, Grace Tiao, Maria T Tusie-Luna, Ben Weisburd, Hong-Hee Won, Dongmei Yu, David M Altshuler, Diego Ardissino, Michael Boehnke, John Danesh, Stacey Donnelly, Roberto Elosua, Jose C Florez, Stacey B Gabriel, Gad Getz, Stephen J Glatt, Christina M Hultman, Sekar Kathiresan, Markku Laakso, Steven McCarroll, Mark I McCarthy, Dermot McGovern, Ruth McPherson, Benjamin M Neale, Aarno Palotie, Shaun M Purcell, Danish Saleheen, Jeremiah M Scharf, Pamela Sklar, Patrick F Sullivan, Jaakko Tuomilehto, Ming T Tsuang, Hugh C Watkins, James G Wilson, Mark J Daly, Daniel G MacArthur
Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence...
August 17, 2016: Nature
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