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https://www.readbyqxmd.com/read/29141314/-a-novel-compound-heterozygous-mutation-in-abca3-gene-in-a-child-with-diffuse-parenchymal-lung-disease
#1
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
#2
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
#3
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
#4
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
#5
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
https://www.readbyqxmd.com/read/29068140/a-founder-mutation-in-cerkl-is-a-major-cause-of-retinal-dystrophy-in-finland
#6
Kristiina Avela, Eeva-Marja Sankila, Sanna Seitsonen, Liina Kuuluvainen, Stephanie Barton, Stuart Gillies, Kristiina Aittomäki
PURPOSE: To study the genetic aetiology of retinal dystrophies (RD) in Finnish patients. METHODS: A targeted next-generation sequencing (NGS) panel of 105 retinal dystrophy genes was used in a cohort of 55 RD patients. RESULTS: The overall diagnostic yield was 60% demonstrating the power of this approach. Interestingly, a missense mutation c.375C>G p.(Cys125Trp) in the CERKL gene was found in 18% of the patients in either a homozygous or compound heterozygous state...
October 25, 2017: Acta Ophthalmologica
https://www.readbyqxmd.com/read/29067606/a-novel-homozygous-1-bp-deletion-in-the-nobox-gene-in-two-brazilian-sisters-with-primary-ovarian-failure
#7
Monica M França, Mariana F A Funari, Antonio M Lerario, Mirian Y Nishi, Carmem C Pita, Eveline G P Fontenele, Berenice B Mendonca
PURPOSE: Primary ovarian failure (POF) is characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women leading to infertility under the age of 40 years. POF is a heterogeneous disease with different causes, and several genes have been associated with the POF phenotype. Thus, Whole-exome sequencing (WES) was performed in a consanguineous family with two sisters affected by POF. METHODS: All exons of both sisters were massively sequenced by WES, and the segregation was confirmed by Sanger sequencing...
October 24, 2017: Endocrine
https://www.readbyqxmd.com/read/29066024/dna-sequencing-and-copy-number-variation-analysis-of-mchr2-in-a-cohort-of-prader-willi-like-pwl-patients
#8
Ellen Geets, Evi Aerts, An Verrijken, Kim Van Hoorenbeeck, Stijn Verhulst, Luc Van Gaal, Wim Van Hul
BACKGROUND: Prader Willi Syndrome (PWS) is a syndromic form of obesity caused by a chromosomal aberration on chromosome 15q11.2-q13. Patients with a comparable phenotype to PWS not carrying the 15q11.2-q13 defect are classified as Prader Willi like (PWL). In literature, PWL patients do frequently harbor deletions at 6q16, which led to the identification of the single-minded 1 (SIM1) gene as a possible cause for the presence of obesity in these patients. However, our previous work in a PWL cohort showed a rather limited involvement of SIM1 in the obesity phenotype...
October 20, 2017: Obesity Research & Clinical Practice
https://www.readbyqxmd.com/read/29044499/identification-of-the-first-homozygous-1-bp-deletion-in-gdf9-gene-leading-to-primary-ovarian-insufficiency-by-using-targeted-massively-parallel-sequencing
#9
M M França, M F A Funari, M Y Nishi, A M Narcizo, S Domenice, E M F Costa, A M Lerario, B B Mendonca
Targeted massively parallel sequencing (TMPS) has been used in genetic diagnosis for Mendelian disorders. In the past few years, the TMPS has identified new and already described genes associated with primary ovarian insufficiency phenotype. Here, we performed a targeted gene sequencing to find a genetic diagnosis in idiopathic cases of Brazilian POI cohort. A custom SureSelect(XT) DNA target enrichment panel was designed and the sequencing was performed on Illumina NextSeq sequencer. We identified one homozygous 1-bp deletion variant (c...
October 16, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/29029963/genetic-risk-factors-in-finnish-patients-with-parkinson-s-disease
#10
Susanna Ylönen, Ari Siitonen, Michael A Nalls, Pauli Ylikotila, Jaana Autere, Johanna Eerola-Rautio, Raphael Gibbs, Mikko Hiltunen, Pentti J Tienari, Hilkka Soininen, Andrew B Singleton, Kari Majamaa
INTRODUCTION: Variation contributing to the risk of Parkinson's disease (PD) has been identified in several genes and at several loci including GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT, but the frequencies of risk variants seem to vary according to ethnic background. Our aim was to analyze how variation in these genes contributes to PD in the Finnish population. METHODS: The subjects consisted of 527 Finnish patients with early-onset PD, 325 patients with late-onset PD and 403 population controls...
September 29, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/29026101/heterozygous-rfx6-protein-truncating-variants-are-associated-with-mody-with-reduced-penetrance
#11
Kashyap A Patel, Jarno Kettunen, Markku Laakso, Alena Stančáková, Thomas W Laver, Kevin Colclough, Matthew B Johnson, Marc Abramowicz, Leif Groop, Päivi J Miettinen, Maggie H Shepherd, Sarah E Flanagan, Sian Ellard, Nobuya Inagaki, Andrew T Hattersley, Tiinamaija Tuomi, Miriam Cnop, Michael N Weedon
Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10(-4))...
October 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/28958595/the-mtdna-replication-related-genes-tfam-and-polg-are-associated-with-leprosy-in-han-chinese-from-southwest-china
#12
Dong Wang, Guo-Dong Li, Yu Fan, Deng-Feng Zhang, Rui Bi, Xiu-Feng Yu, Heng Long, Yu-Ye Li, Yong-Gang Yao
BACKGROUND: The pathogen Mycobacterium leprae of leprosy is heavily dependent on the host energy metabolites and nutritional products for survival. Previously we and others have identified associations of several mitochondrion-related genes and mitochondrial DNA (mtDNA) copy number alterations with leprosy and/or its subtype. We hypothesized that genetic variants of mtDNA replication-related genes would affect leprosy. OBJECTIVE: We aimed to identify genetic associations between the mtDNA replication-related genes TFAM, POLG and leprosy...
September 14, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28945736/rapid-functional-analysis-of-computationally-complex-rare-human-irf6-gene-variants-using-a-novel-zebrafish-model
#13
Edward B Li, Dawn Truong, Shawn A Hallett, Kusumika Mukherjee, Brian C Schutte, Eric C Liao
Large-scale sequencing efforts have captured a rapidly growing catalogue of genetic variations. However, the accurate establishment of gene variant pathogenicity remains a central challenge in translating personal genomics information to clinical decisions. Interferon Regulatory Factor 6 (IRF6) gene variants are significant genetic contributors to orofacial clefts. Although approximately three hundred IRF6 gene variants have been documented, their effects on protein functions remain difficult to interpret. Here, we demonstrate the protein functions of human IRF6 missense gene variants could be rapidly assessed in detail by their abilities to rescue the irf6 -/- phenotype in zebrafish through variant mRNA microinjections at the one-cell stage...
September 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28944233/protein-structure-and-phenotypic-analysis-of-pathogenic-and-population-missense-variants-in-stxbp1
#14
Mohnish Suri, Jochem M G Evers, Roman A Laskowski, Sinead O'Brien, Kate Baker, Jill Clayton-Smith, Tabib Dabir, Dragana Josifova, Shelagh Joss, Bronwyn Kerr, Alison Kraus, Meriel McEntagart, Jenny Morton, Audrey Smith, Miranda Splitt, Janet M Thornton, Caroline F Wright
BACKGROUND: Syntaxin-binding protein 1, encoded by STXBP1, is highly expressed in the brain and involved in fusing synaptic vesicles with the plasma membrane. Studies have shown that pathogenic loss-of-function variants in this gene result in various types of epilepsies, mostly beginning early in life. We were interested to model pathogenic missense variants on the protein structure to investigate the mechanism of pathogenicity and genotype-phenotype correlations. METHODS: We report 11 patients with pathogenic de novo mutations in STXBP1 identified in the first 4293 trios of the Deciphering Developmental Disorder (DDD) study, including six missense variants...
September 2017: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/28926565/a-snp-panel-and-online-tool-for-checking-genotype-concordance-through-comparing-qr-codes
#15
Yonghong Du, Joshua S Martin, John McGee, Yuchen Yang, Eric Yi Liu, Yingrui Sun, Matthias Geihs, Xuejun Kong, Eric Lingfeng Zhou, Yun Li, Jie Huang
In the current precision medicine era, more and more samples get genotyped and sequenced. Both researchers and commercial companies expend significant time and resources to reduce the error rate. However, it has been reported that there is a sample mix-up rate of between 0.1% and 1%, not to mention the possibly higher mix-up rate during the down-stream genetic reporting processes. Even on the low end of this estimate, this translates to a significant number of mislabeled samples, especially over the projected one billion people that will be sequenced within the next decade...
2017: PloS One
https://www.readbyqxmd.com/read/28905877/population-specific-genetic-variation-in-large-sequencing-data-sets-why-more-data-is-still-better
#16
Jeroen G J van Rooij, Mila Jhamai, Pascal P Arp, Stephan C A Nouwens, Marijn Verkerk, Albert Hofman, M Arfan Ikram, Annemieke J Verkerk, Joyce B J van Meurs, Fernando Rivadeneira, André G Uitterlinden, Robert Kraaij
We have generated a next-generation whole-exome sequencing data set of 2628 participants of the population-based Rotterdam Study cohort, comprising 669 737 single-nucleotide variants and 24 019 short insertions and deletions. Because of broad and deep longitudinal phenotyping of the Rotterdam Study, this data set permits extensive interpretation of genetic variants on a range of clinically relevant outcomes, and is accessible as a control data set. We show that next-generation sequencing data sets yield a large degree of population-specific variants, which are not captured by other available large sequencing efforts, being ExAC, ESP, 1000G, UK10K, GoNL and DECODE...
October 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28888541/frequency-of-mutations-in-a-large-series-of-clinically-ascertained-ovarian-cancer-cases-tested-on-multi-gene-panels-compared-to-reference-controls
#17
Jenna Lilyquist, Holly LaDuca, Eric Polley, Brigette Tippin Davis, Hermela Shimelis, Chunling Hu, Steven N Hart, Jill S Dolinsky, Fergus J Couch, David E Goldgar
OBJECTIVES: Given the lack of adequate screening modalities, knowledge of ovarian cancer risks for carriers of pathogenic alterations in predisposition genes is important for decisions about risk-reduction by salpingo-oophorectomy. We sought to determine which genes assayed on multi-gene panels are associated with ovarian cancer, the magnitude of the associations, and for which clinically meaningful associations could be ruled out. METHODS: 7768 adult ovarian cancer cases of European ancestry referred to a single clinical testing laboratory underwent multi-gene panel testing for detection of pathogenic alterations in known or suspected ovarian cancer susceptibility genes...
November 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28870863/use-of-targeted-sequence-capture-and-high-throughput-sequencing-identifies-a-novel-pkd1-mutation-involved-in-adult-polycystic-kidney-disease
#18
Yan-Kun Sha, Yan-Wei Sha, Li-Bin Mei, Xian-Jing Huang, Xu Wang, Shao-Bin Lin, Lin Li, Ping Li
Polycystic kidney disease (PKD) is a common inherited disease that is characterized by a progressive development of renal cysts. Approximately 85% of PKD cases are due to mutations in the polycystin 1 (PKD1) gene. Here, we report a pedigree containing nine patients with autosomal dominant PKD (ADPKD). Using targeted exome sequencing of PKD1 and PKD2 genes, we identified a novel heterozygous frameshift mutation c.3976_3977insCT (p.F1326Sfs*21) in the PKD1 gene that segregated between affected and unaffected family members...
November 15, 2017: Gene
https://www.readbyqxmd.com/read/28771248/interpreting-the-clinical-significance-of-combined-variants-in-multiple-recessive-disease-genes-systematic-investigation-of-joubert-syndrome-yields-little-support-for-oligogenicity
#19
Ian G Phelps, Jennifer C Dempsey, Megan E Grout, Christine R Isabella, Hannah M Tully, Dan Doherty, Ruxandra Bachmann-Gagescu
PurposeNext-generation sequencing (NGS) often identifies multiple rare predicted-deleterious variants (RDVs) in different genes associated with a recessive disorder in a given patient. Such variants have been proposed to contribute to digenicity/oligogenicity or "triallelism" or to act as genetic modifiers.MethodsUsing the recessive ciliopathy Joubert syndrome (JBTS) as a model, we investigated these possibilities systematically, relying on NGS of known JBTS genes in a large JBTS and two control cohorts.Results65% of affected individuals had a recessive genetic cause, while 4...
August 3, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/28759051/implications-of-human-genetic-variation-in-crispr-based-therapeutic-genome-editing
#20
David A Scott, Feng Zhang
CRISPR-Cas genome-editing methods hold immense potential as therapeutic tools to fix disease-causing mutations at the level of DNA. In contrast to typical drug development strategies aimed at targets that are highly conserved among individual patients, treatment at the genomic level must contend with substantial inter-individual natural genetic variation. Here we analyze the recently released ExAC and 1000 Genomes data sets to determine how human genetic variation impacts target choice for Cas endonucleases in the context of therapeutic genome editing...
September 2017: Nature Medicine
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