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https://www.readbyqxmd.com/read/28518168/using-high-resolution-variant-frequencies-to-empower-clinical-genome-interpretation
#1
Nicola Whiffin, Eric Minikel, Roddy Walsh, Anne H O'Donnell-Luria, Konrad Karczewski, Alexander Y Ing, Paul J R Barton, Birgit Funke, Stuart A Cook, Daniel MacArthur, James S Ware
PurposeWhole-exome and whole-genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognized as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants...
May 18, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/28512196/the-developmental-biology-of-genetic-notch-disorders
#2
REVIEW
Jan Mašek, Emma R Andersson
Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands lead to a variety of congenital disorders in humans. For example, loss of function of Notch results in Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis and congenital heart disorders, while Notch gain of function results in Hajdu-Cheney syndrome, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis and lateral meningocele syndrome...
May 15, 2017: Development
https://www.readbyqxmd.com/read/28505210/whole-exome-sequencing-of-a-consanguineous-family-identifies-the-possible-modifying-effect-of-a-globally-rare-ak5-allelic-variant-in-celiac-disease-development-among-saudi-patients
#3
Jumana Yousuf Al-Aama, Noor Ahmad Shaik, Babajan Banaganapalli, Mohammed A Salama, Omran Rashidi, Ahmed N Sahly, Mohammed O Mohsen, Harbi A Shawoosh, Hebah Ahmad Shalabi, Mohammad Al Edreesi, Sameer E Alharthi, Jun Wang, Ramu Elango, Omar I Saadah
Celiac disease (CD), a multi-factorial auto-inflammatory disease of the small intestine, is known to occur in both sporadic and familial forms. Together HLA and Non-HLA genes can explain up to 50% of CD's heritability. In order to discover the missing heritability due to rare variants, we have exome sequenced a consanguineous Saudi family presenting CD in an autosomal recessive (AR) pattern. We have identified a rare homozygous insertion c.1683_1684insATT, in the conserved coding region of AK5 gene that showed classical AR model segregation in this family...
2017: PloS One
https://www.readbyqxmd.com/read/28502612/marrvel-integration-of-human-and-model-organism-genetic-resources-to-facilitate-functional-annotation-of-the-human-genome
#4
Julia Wang, Rami Al-Ouran, Yanhui Hu, Seon-Young Kim, Ying-Wooi Wan, Michael F Wangler, Shinya Yamamoto, Hsiao-Tuan Chao, Aram Comjean, Stephanie E Mohr, Norbert Perrimon, Zhandong Liu, Hugo J Bellen
One major challenge encountered with interpreting human genetic variants is the limited understanding of the functional impact of genetic alterations on biological processes. Furthermore, there remains an unmet demand for an efficient survey of the wealth of information on human homologs in model organisms across numerous databases. To efficiently assess the large volume of publically available information, it is important to provide a concise summary of the most relevant information in a rapid user-friendly format...
May 3, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28487536/common-sequence-variants-affect-molecular-function-more-than-rare-variants
#5
Yannick Mahlich, Jonas Reeb, Maximilian Hecht, Maria Schelling, Tjaart Andries Petrus De Beer, Yana Bromberg, Burkhard Rost
Any two unrelated individuals differ by about 10,000 single amino acid variants (SAVs). Do these impact molecular function? Experimental answers cannot answer comprehensively, while state-of-the-art prediction methods can. We predicted the functional impacts of SAVs within human and for variants between human and other species. Several surprising results stood out. Firstly, four methods (CADD, PolyPhen-2, SIFT, and SNAP2) agreed within 10 percentage points on the percentage of rare SAVs predicted with effect...
May 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28471432/assessment-of-the-exac-data-set-for-the-presence-of-individuals-with-pathogenic-genotypes-implicated-in-severe-mendelian-pediatric-disorders
#6
Maja Tarailo-Graovac, Jing Yun Alice Zhu, Allison Matthews, Clara D M van Karnebeek, Wyeth W Wasserman
PurposeWe analyzed the Exome Aggregation Consortium (ExAC) data set for the presence of individuals with pathogenic genotypes implicated in Mendelian pediatric disorders.MethodsClinVar likely/pathogenic variants supported by at least one peer-reviewed publication were assessed within the ExAC database to identify individuals expected to exhibit a childhood disorder based on concordance with disease inheritance modes: heterozygous (for dominant), homozygous (for recessive) or hemizygous (for X-linked recessive conditions)...
May 4, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/28456503/novel-oxytocin-receptor-variants-in-laboring-women-requiring-high-doses-of-oxytocin
#7
Erin L Reinl, Zane A Goodwin, Nandini Raghuraman, Grace Y Lee, Erin Y Jo, Beakal M Gezahegn, Meghan K Pillai, Alison G Cahill, Cristina De Guzman Strong, Sarah K England
BACKGROUND: Although oxytocin commonly is used to augment or induce labor, it is difficult to predict its effectiveness because oxytocin dose requirements vary significantly among women. One possibility is that women requiring high or low doses of oxytocin have variations in the oxytocin receptor gene. OBJECTIVES: To identify oxytocin receptor gene variants in laboring women with low and high oxytocin dosage requirements. STUDY DESIGN: Term, nulliparous women requiring oxytocin doses of ≤4 mU/min (low-dose requiring, n = 83) or ≥20 mU/min (high-dose requiring, n = 104) for labor augmentation or induction provided consent to a postpartum blood draw as a source of genomic DNA...
April 26, 2017: American Journal of Obstetrics and Gynecology
https://www.readbyqxmd.com/read/28427458/whole-exome-sequencing-identifies-novel-candidate-predisposition-genes-for-familial-polycythemia-vera
#8
Elina A M Hirvonen, Esa Pitkänen, Kari Hemminki, Lauri A Aaltonen, Outi Kilpivaara
BACKGROUND: Polycythemia vera (PV), characterized by massive production of erythrocytes, is one of the myeloproliferative neoplasms. Most patients carry a somatic gain-of-function mutation in JAK2, c.1849G > T (p.Val617Phe), leading to constitutive activation of JAK-STAT signaling pathway. Familial clustering is also observed occasionally, but high-penetrance predisposition genes to PV have remained unidentified. RESULTS: We studied the predisposition to PV by exome sequencing (three cases) in a Finnish PV family with four patients...
April 20, 2017: Human Genomics
https://www.readbyqxmd.com/read/28377322/caution-in-interpretation-of-disease-causality-for-heterozygous-loss-of-function-variants-in-the-myh8-gene-associated-with-autosomal-dominant-disorder
#9
Zunyan Dai, Zachary Whitt, Lindsey C Mighion, Alessandro Pontoglio, Lora J H Bean, Roberto Colombo, Madhuri Hegde
To date, the NM_002472.2(MYH8):c.2021G>A (p.Arg674Gln) missense variant in the MYH8 gene is the only known genetic change in individuals with autosomal dominant trismus-pseudocamptodactyly syndrome with unknown molecular mechanism. Next-generation sequencing (NGS), including targeted gene panels and whole-exome sequencing, is routinely performed in many clinical diagnostic laboratories as standard-of-care testing aimed at identifying disease-causing genomic variants. Whole-exome sequencing has revealed loss-of-function variants in the MYH8 gene...
June 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28356211/pkd2-related-autosomal-dominant-polycystic-kidney-disease-prevalence-clinical-presentation-mutation-spectrum-and%C3%A2-prognosis
#10
Emilie Cornec-Le Gall, Marie-Pierre Audrézet, Eric Renaudineau, Maryvonne Hourmant, Christophe Charasse, Eric Michez, Thierry Frouget, Cécile Vigneau, Jacques Dantal, Pascale Siohan, Hélène Longuet, Philippe Gatault, Laure Ecotière, Frank Bridoux, Lise Mandart, Catherine Hanrotel-Saliou, Corina Stanescu, Pascale Depraetre, Sophie Gie, Michiel Massad, Aude Kersalé, Guillaume Séret, Jean-François Augusto, Philippe Saliou, Sandrine Maestri, Jian-Min Chen, Peter C Harris, Claude Férec, Yannick Le Meur
BACKGROUND: PKD2-related autosomal dominant polycystic kidney disease (ADPKD) is widely acknowledged to be of milder severity than PKD1-related disease, but population-based studies depicting the exact burden of the disease are lacking. We aimed to revisit PKD2 prevalence, clinical presentation, mutation spectrum, and prognosis through the Genkyst cohort. STUDY DESIGN: Case series, January 2010 to March 2016. SETTINGS & PARTICIPANTS: Genkyst study participants are individuals older than 18 years from 22 nephrology centers from western France with a diagnosis of ADPKD based on Pei criteria or at least 10 bilateral kidney cysts in the absence of a familial history...
March 26, 2017: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
https://www.readbyqxmd.com/read/28302154/the-israeli-national-genetic-database-a-10-year-experience
#11
Joël Zlotogora, George P Patrinos
BACKGROUND: The Israeli National and Ethnic Mutation database ( http://server.goldenhelix.org/israeli ) was launched in September 2006 on the ETHNOS software to include clinically relevant genomic variants reported among Jewish and Arab Israeli patients. In 2016, the database was reviewed and corrected according to ClinVar ( https://www.ncbi.nlm.nih.gov/clinvar ) and ExAC ( http://exac.broadinstitute.org ) database entries. The present article summarizes some key aspects from the development and continuous update of the database over a 10-year period, which could serve as a paradigm of successful database curation for other similar resources...
March 16, 2017: Human Genomics
https://www.readbyqxmd.com/read/28279756/analysis-of-ccr5-gene-polymorphisms-in-321-healthy-saudis-using-next-generation-sequencing
#12
Mohammed A Al Balwi, Ali I Hadadi, Wardah Alharbi, Mariam Ballow, Abdulrahman AlAsiri, Abdulkareem AlAbdulrahman, Udayaraja G K, Mohammed Aldrees, Ibrahim AlAbdulkareem, Ali H Hajeer
AIMS: To investigate the extent of CCR5 polymorphism in the healthy Saudi population. METHOD: A total of 321 healthy Saudi individuals were sequenced using the ion Ampliseq™ Exome kit (Life Technologies, USA) on genomic DNA following manufacturer's protocol. Whole Exome Sequencing (WES) reads were aligned to the human reference genome (hg19 build) with Torrent Suite Software (v5.0.2) and the variants were called using the Torrent Variant Caller plugin (v5.0) and imported into Ion Reporter Server (v5...
April 2017: Human Immunology
https://www.readbyqxmd.com/read/28276201/rare-deleterious-variants-in-grhl3-are-associated-with-human-spina-bifida
#13
Philippe Lemay, Patrizia De Marco, Alexandre Emond, Dan Spiegelman, Alexandre Dionne-Laporte, Sandra Laurent, Elisa Merello, Andrea Accogli, Guy A Rouleau, Valeria Capra, Zoha Kibar
Neural tube defects, including spina bifida, are among the most common birth defects caused by failure of neural tube closure during development. They have a complex etiology involving largely undetermined environmental and genetic factors. Previous studies in mouse models have implicated the transcription factor Grhl3 as an important factor in the pathogenesis of spina bifida. In the present study, we conducted a resequencing analysis of GRHL3 in a cohort of 233 familial and sporadic cases of spina bifida...
June 2017: Human Mutation
https://www.readbyqxmd.com/read/28259467/genetic-variants-of-the-dna-repair-genes-from-exome-aggregation-consortium-exac-database-significance-in-cancer
#14
Raima Das, Sankar Kumar Ghosh
DNA repair pathway is a primary defense system that eliminates wide varieties of DNA damage. Any deficiencies in them are likely to cause the chromosomal instability that leads to cell malfunctioning and tumorigenesis. Genetic polymorphisms in DNA repair genes have demonstrated a significant association with cancer risk. Our study attempts to give a glimpse of the overall scenario of the germline polymorphisms in the DNA repair genes by taking into account of the Exome Aggregation Consortium (ExAC) database as well as the Human Gene Mutation Database (HGMD) for evaluating the disease link, particularly in cancer...
February 22, 2017: DNA Repair
https://www.readbyqxmd.com/read/28245912/mutational-screening-in-genes-related-with-porto-pulmonary-hypertension-an-analysis-of-6-cases
#15
Guillermo Pousada, Adolfo Baloira, Diana Valverde
INTRODUCTION: Portopulmonary hypertension (PPH) is a rare disease with a low incidence and without a clearly-identified genetic component. The aim of this work was to check genes and genetic modifiers related to pulmonary arterial hypertension in patients with PPH in order to clarify the molecular basis of the pathology. PATIENTS: We selected a total of 6 patients with PPH and amplified the exonic regions and intronic flanking regions of the relevant genes and regions of interest of the genetic modifiers...
April 7, 2017: Medicina Clínica
https://www.readbyqxmd.com/read/28241850/accurate-and-equitable-medical-genomic-analysis-requires-an-understanding-of-demography-and-its-influence-on-sample-size-and-ratio
#16
Michael D Kessler, Timothy D O'Connor
In a recent study, Petrovski and Goldstein reported that (non-Finnish) Europeans have significantly fewer nonsynonymous singletons in Online Mendelian Inheritance in Man (OMIM) disease genes compared with Africans, Latinos, South Asians, East Asians, and other unassigned non-Europeans. We use simulations of Exome Aggregation Consortium (ExAC) data to show that sample size and ratio interact to influence the number of these singletons identified in a cohort. These interactions are different across ancestries and can lead to the same number of identified singletons in both Europeans and non-Europeans without an equal number of samples...
February 27, 2017: Genome Biology
https://www.readbyqxmd.com/read/28229513/pathogenic-asxl1-somatic-variants-in-reference-databases-complicate-germline-variant-interpretation-for-bohring-opitz-syndrome
#17
Colleen M Carlston, Anne H O'Donnell-Luria, Hunter R Underhill, Beryl B Cummings, Ben Weisburd, Eric V Minikel, Daniel P Birnbaum, Tatiana Tvrdik, Daniel G MacArthur, Rong Mao
The clinical interpretation of genetic variants has come to rely heavily on reference population databases such as the Exome Aggregation Consortium (ExAC) database. Pathogenic variants in genes associated with severe, pediatric-onset, highly penetrant, autosomal dominant conditions are assumed to be absent or rare in these databases. Exome sequencing of a 6-year-old female patient with seizures, developmental delay, dysmorphic features, and failure to thrive identified an ASXL1 variant previously reported as causative of Bohring-Opitz syndrome (BOS)...
May 2017: Human Mutation
https://www.readbyqxmd.com/read/28228119/genetic-variation-of-the-toll-like-receptors-in-a-swedish-allergic-rhinitis-case-population
#18
V Henmyr, D Carlberg, E Manderstedt, C Lind-Halldén, T Säll, L O Cardell, C Halldén
BACKGROUND: Variation in the 10 toll-like receptor (TLR) genes has been significantly associated with allergic rhinitis (AR) in several candidate gene studies and three large genome-wide association studies. These have all investigated common variants, but no investigations for rare variants (MAF ≤ 1%) have been made in AR. The present study aims to describe the genetic variation of the promoter and coding sequences of the 10 TLR genes in 288 AR patients. METHODS: Sanger sequencing and Ion Torrent next-generation sequencing was used to identify polymorphisms in a Swedish AR population and these were subsequently compared and evaluated using 1000Genomes and Exome Aggregation Consortium (ExAC) data...
February 23, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28166811/pathogenic-variant-burden-in-the-exac-database-an-empirical-approach-to-evaluating-population-data-for-clinical-variant-interpretation
#19
Yuya Kobayashi, Shan Yang, Keith Nykamp, John Garcia, Stephen E Lincoln, Scott E Topper
BACKGROUND: The frequency of a variant in the general population is a key criterion used in the clinical interpretation of sequence variants. With certain exceptions, such as founder mutations, the rarity of a variant is a prerequisite for pathogenicity. However, defining the threshold at which a variant should be considered "too common" is challenging and therefore diagnostic laboratories have typically set conservative allele frequency thresholds. METHODS: Recent publications of large population sequencing data, such as the Exome Aggregation Consortium (ExAC) database, provide an opportunity to characterize with accuracy and precision the frequency distributions of very rare disease-causing alleles...
February 6, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28152038/exome-sequencing-covers-98-of-mutations-identified-on-targeted-next-generation-sequencing-panels
#20
Holly LaDuca, Kelly D Farwell, Huy Vuong, Hsiao-Mei Lu, Wenbo Mu, Layla Shahmirzadi, Sha Tang, Jefferey Chen, Shruti Bhide, Elizabeth C Chao
BACKGROUND: With the expanded availability of next generation sequencing (NGS)-based clinical genetic tests, clinicians seeking to test patients with Mendelian diseases must weigh the superior coverage of targeted gene panels with the greater number of genes included in whole exome sequencing (WES) when considering their first-tier testing approach. Here, we use an in silico analysis to predict the analytic sensitivity of WES using pathogenic variants identified on targeted NGS panels as a reference...
2017: PloS One
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