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https://www.readbyqxmd.com/read/29458007/a-genomically-characterized-collection-of-high-grade-serous-ovarian-cancer-xenografts-for-preclinical-testing
#1
Paulina Cybulska, Jocelyn M Stewart, Azin Sayad, Carl Virtanen, Patricia A Shaw, Blaise Clarke, Natalie Stickle, Marcus Q Bernardini, Benjamin G Neel
High-grade serous ovarian cancer (HGSC) is the leading cause of morbidity and mortality from gynecologic malignancy. Overall survival remains low, due to the nearly ubiquitous emergence of platinum-resistance and the paucity of effective next-line treatments. Current cell culture-based models show limited similarity to HGSC and are therefore unreliable predictive models for pre-clinical evaluation of investigational drugs. This deficiency could help explain the low overall rate of successful drug development and the decades of largely unchanged approaches to HGSC treatment...
February 16, 2018: American Journal of Pathology
https://www.readbyqxmd.com/read/29456480/novel-homozygous-missense-mutation-in-ryr1-leads-to-severe-congenital-ptosis-ophthalmoplegia-and-scoliosis-in-the-absence-of-myopathy
#2
Nafi Dilaver, Neda Mazaheri, Reza Maroofian, Jawaher Zeighami, Tahere Seifi, Mina Zamani, Alireza Sedaghat, Gholam Reza Shariati, Hamid Galehdari
Ryanodine receptor 1 ( RYR1 ) is an intracellular calcium receptor primarily expressed in skeletal muscle with a role in excitation contraction. Both dominant and recessive mutations in the RYR1 gene cause a range of RYR1 -related myopathies and/or susceptibility to malignant hyperthermia (MH). Recently, an atypical manifestation of ptosis, variably presenting with ophthalmoplegia, facial paralysis, and scoliosis but without significant muscle weakness, has been reported in 9 cases from 4 families with bialleic variants in RYR1 ...
December 2017: Molecular Syndromology
https://www.readbyqxmd.com/read/29455859/heterozygous-mutations-in-oas1-cause-infantile-onset-pulmonary-alveolar-proteinosis-with-hypogammaglobulinemia
#3
Kazutoshi Cho, Masafumi Yamada, Kazunaga Agematsu, Hirokazu Kanegane, Noriko Miyake, Masahiro Ueki, Takuma Akimoto, Norimoto Kobayashi, Satoru Ikemoto, Mishie Tanino, Atsushi Fujita, Itaru Hayasaka, Satoshi Miyamoto, Mari Tanaka-Kubota, Koh Nakata, Masaaki Shiina, Kazuhiro Ogata, Hisanori Minakami, Naomichi Matsumoto, Tadashi Ariga
Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of a surfactant-like substance in alveolar spaces and hypoxemic respiratory failure. Genetic PAP (GPAP) is caused by mutations in genes encoding surfactant proteins or genes encoding a surfactant phospholipid transporter in alveolar type II epithelial cells. GPAP is also caused by mutations in genes whose products are implicated in surfactant catabolism in alveolar macrophages (AMs). We performed whole-exome sequence analysis in a family affected by infantile-onset PAP with hypogammaglobulinemia without causative mutations in genes associated with PAP: SFTPB, SFTPC, ABCA3, CSF2RA, CSF2RB, and GATA2...
February 12, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29454792/clinical-and-genomic-correlates-of-neutrophil-reactive-oxygen-species-production-in-pediatric-patients-with-crohn-s-disease
#4
Lee A Denson, Ingrid Jurickova, Rebekah Karns, Kelly A Shaw, David J Cutler, David Okou, Anne Dodd, Kathryn Quinn, Kajari Mondal, Bruce J Aronow, Yael Haberman, Aaron Linn, Adam Price, Ramona Bezold, Kathleen Lake, Kimberly Jackson, 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 L Guthery, Marla C Dubinsky, Neal S Leleiko, Anthony R Otley, Ramnik J Xavier, Christine Stevens, Mark J Daly, Michael E Zwick, Subra Kugathasan
BACKGROUND & AIMS: Individuals with monogenic disorders of phagocyte function develop chronic colitis that resembles Crohn's Disease (CD). We tested for associations between mutations in genes encoding NADPH oxidases, neutrophil function, and phenotypes of CD in pediatric patients. METHODS: We performed whole-exome sequence analysis to identify mutations in genes encoding NADPH oxidases (such as CYBA, CYBB, NCF1, NCF2, NCF4, RAC1, and RAC2) using DNA from 543 pediatric patients with inflammatory bowel diseases...
February 15, 2018: Gastroenterology
https://www.readbyqxmd.com/read/29453956/frequent-mutations-of-retnet-genes-in-eohm-further-confirmation-in-325-probands-and-comparison-with-late-onset-high-myopia-based-on-exome-sequencing
#5
Lin Zhou, Xueshan Xiao, Shiqiang Li, Xiaoyun Jia, Qingjiong Zhang
In our previous study, potential pathological mutations of RetNet genes were detected in 23.8% (71/298) of probands with early-onset high myopia (eoHM), based on whole exome sequencing (WES). The current study aimed to confirm this finding in an additional 325 probands with eoHM and to clarify its specificity by comparison of 195 probands with late-onset high myopia (loHM). Variants in the 234 RetNet genes were selected from whole-exome sequencing data and were filtered using multistep bioinformatics analyses...
February 14, 2018: Experimental Eye Research
https://www.readbyqxmd.com/read/29453856/defective-rna-sensing-by-rig-i-in-severe-influenza-virus-infection
#6
Sofie Eg Jørgensen, Mette Christiansen, Laura Barrett Ryø, Hans Henrik Gad, Jakob Gjedsted, Peter Staeheli, Jacob Giehm Mikkelsen, Merete Storgaard, Rune Hartmann, Trine Hyrup Mogensen
Influenza virus infection causes worldwide seasonal epidemics. Although influenza usually is a mild disease, a minority of patients experience very severe fulminating disease courses. Previous studies have demonstrated a role for type I interferon (IFN) in antiviral responses during influenza. However, IFN regulatory factor (IRF)7 deficiency is so far the only genetic cause of severe influenza described in humans. In this study we present a patient with severe influenza A virus (IAV) H1N1 infection during the 2009 Swine Flu pandemic...
February 17, 2018: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/29453517/probable-diagnosis-of-a-patient-with-niemann-pick-disease-type-c-managing-pitfalls-of-exome-sequencing
#7
William A Zeiger, Nasheed I Jamal, Maren T Scheuner, Patricia Pittman, Kimiyo M Raymond, Massimo Morra, Shri K Mishra
Here, we present a case of a 31-year-old man with progressive cognitive decline, ataxia, and dystonia. Extensive laboratory, radiographic, and targeted genetic studies over the course of several years failed to yield a diagnosis. Initial whole exome sequencing through a commercial laboratory identified several variants of uncertain significance; however, follow-up clinical examination and testing ruled each of these out. Eventually, repeat whole exome sequencing identified a known pathogenic intronic variant in the NPC1 gene (NM_000271...
February 17, 2018: JIMD Reports
https://www.readbyqxmd.com/read/29453510/next-generation-metabolic-screening-targeted-and-untargeted-metabolomics-for-the-diagnosis-of-inborn-errors-of-metabolism-in-individual-patients
#8
Karlien L M Coene, Leo A J Kluijtmans, Ed van der Heeft, Udo F H Engelke, Siebolt de Boer, Brechtje Hoegen, Hanneke J T Kwast, Maartje van de Vorst, Marleen C D G Huigen, Irene M L W Keularts, Michiel F Schreuder, Clara D M van Karnebeek, Saskia B Wortmann, Maaike C de Vries, Mirian C H Janssen, Christian Gilissen, Jasper Engel, Ron A Wevers
The implementation of whole-exome sequencing in clinical diagnostics has generated a need for functional evaluation of genetic variants. In the field of inborn errors of metabolism (IEM), a diverse spectrum of targeted biochemical assays is employed to analyze a limited amount of metabolites. We now present a single-platform, high-resolution liquid chromatography quadrupole time of flight (LC-QTOF) method that can be applied for holistic metabolic profiling in plasma of individual IEM-suspected patients. This method, which we termed "next-generation metabolic screening" (NGMS), can detect >10,000 features in each sample...
February 16, 2018: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/29453417/exome-sequencing-has-higher-diagnostic-yield-compared-to-simulated-disease-specific-panels-in-children-with-suspected-monogenic-disorders
#9
Oliver James Dillon, Sebastian Lunke, Zornitza Stark, Alison Yeung, Natalie Thorne, Clara Gaff, Susan M White, Tiong Yang Tan
As test costs decline, whole-exome sequencing (WES) has become increasingly used for clinical diagnosis, and now represents the primary alternative to gene panel testing for patients with a suspected genetic disorder. We sought to compare the diagnostic yield of singleton-WES with simulated application of commercial gene panels in children suspected of having a genetically heterogeneous condition. Recruitment, singleton-WES and phenotype-driven variant analysis was completed for 145 paediatric patients. At recruitment, clinicians were required to propose commercial gene panel tests as an alternative to WES and nominate a phenotype-driven candidate gene list...
February 16, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29453416/homozygous-deletion-in-myl9-expands-the-molecular-basis-of-megacystis-microcolon-intestinal-hypoperistalsis-syndrome
#10
Carolina Araujo Moreno, Nara Sobreira, Elizabeth Pugh, Peng Zhang, Gary Steel, Fábio Rossi Torres, Denise Pontes Cavalcanti
Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a severe disease characterized by functional obstruction in the urinary and gastrointestinal tract. The molecular basis of this condition started to be defined recently, and the genes related to the syndrome (ACTG2-heterozygous variant in sporadic cases; and MYH11 (myosin heavy chain 11), LMOD1 (leiomodin 1) and MYLK (myosin light chain (MLC) kinase)-autosomal recessive inheritance), encode proteins involved in the smooth muscle contraction, supporting a myopathic basis for the disease...
February 16, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29453415/erlin1-mutations-cause-teenage-onset-slowly-progressive-als-in-a-large-turkish-pedigree
#11
Ceren Tunca, Fulya Akçimen, Cemre Coşkun, Aslı Gündoğdu-Eken, Cemile Kocoglu, Betül Çevik, Can Ebru Bekircan-Kurt, Ersin Tan, A Nazlı Başak
Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease with mostly dominant inheritance and a life expectancy of 2-5 years; however, a quite common occurrence of atypical forms of the disease, due to recessive inheritance, has become evident with the use of NGS technologies. In this paper, we describe a family with close consanguinity for at least four generations, suffering from a slowly progressive form of ALS. Spastic walking is observed since teenage years, while bulbar symptoms start much later, at the fifth or sixth decade of life...
February 16, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29453195/mutation-of-ifnlr1-an-interferon-lambda-receptor-1-is-associated-with-autosomal-dominant-non-syndromic-hearing-loss
#12
Xue Gao, Yong-Yi Yuan, Qiong-Fen Lin, Jin-Cao Xu, Wei-Qian Wang, Yue-Hua Qiao, Dong-Yang Kang, Dan Bai, Feng Xin, Sha-Sha Huang, Shi-Wei Qiu, Li-Ping Guan, Yu Su, Guo-Jian Wang, Ming-Yu Han, Yi Jiang, Han-Kui Liu, Pu Dai
Background Hereditary sensorineural hearing loss is a genetically heterogeneous disorder. Objectives This study was designed to explore the genetic etiology of deafness in a large Chinese family with autosomal dominant, nonsyndromic, progressive sensorineural hearing loss (ADNSHL). Methods Whole exome sequencing and linkage analysis were performed to identify pathogenic mutation. Inner ear expression of Ifnlr1 was investigated by immunostaining in mice. ifnlr1 Morpholino knockdown Zebrafish were constructed to explore the deafness mechanism...
February 16, 2018: Journal of Medical Genetics
https://www.readbyqxmd.com/read/29452748/knockout-of-human-muscle-genes-revealed-by-large-scale-whole-exome-studies
#13
Stefano Schiaffino
Large scale whole-exome sequence studies have revealed that a number of individuals from different populations have predicted loss-of-function of different genes due to nonsense, frameshift, or canonical splice-site mutations. Surprisingly, many of these mutations do not apparently show the deleterious phenotypic consequences expected from gene knockout. These homozygous null mutations, when confirmed, can provide insight into human gene function and suggest novel approaches to correct gene dysfunction, as the lack of the expected disease phenotype may reflect the existence of modifier genes that reveal potential therapeutic targets...
February 10, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29452367/variant-in-human-pofut1-reduces-enzymatic-activity-and-likely-causes-a-recessive-microcephaly-global-developmental-delay-with-cardiac-and-vascular-features
#14
Hideyuki Takeuchi, Derek Wong, Michael Schneider, Hudson H Freeze, Megumi Takeuchi, Steven J Berardinelli, Atsuko Ito, Hane Lee, Stanley F Nelson, Robert S Haltiwanger
Protein O-fucosyltransferase-1 (POFUT1) adds O-fucose monosaccharides to epidermal growth factor-like (EGF) repeats found on approximately 100 mammalian proteins, including Notch receptors. Haploinsufficiency of POFUT1 has been linked to adult-onset Dowling Degos Disease (DDD) with hyperpigmentation defects. Homozygous deletion of mouse Pofut1 results in embryonic lethality with severe Notch-like phenotypes including defects in somitogenesis, cardiogenesis, vasculogenesis, and neurogenesis, but the extent to which POFUT1 is required for normal human development is not yet understood...
February 14, 2018: Glycobiology
https://www.readbyqxmd.com/read/29451896/hypomyelinating-disorders-in-china-the-clinical-and-genetic-heterogeneity-in-119-patients
#15
Haoran Ji, Dongxiao Li, Ye Wu, Quanli Zhang, Qiang Gu, Han Xie, Taoyun Ji, Huifang Wang, Lu Zhao, Haijuan Zhao, Yanling Yang, Hongchun Feng, Hui Xiong, Jinhua Ji, Zhixian Yang, Liping Kou, Ming Li, Xinhua Bao, Xingzhi Chang, Yuehua Zhang, Li Li, Huijuan Li, Zhengping Niu, Xiru Wu, Jiangxi Xiao, Yuwu Jiang, Jingmin Wang
OBJECTIVE: Hypomyelinating disorders are a group of clinically and genetically heterogeneous diseases characterized by neurological deterioration with hypomyelination visible on brain MRI scans. This study was aimed to clarify the clinical and genetic features of HMDs in Chinese population. METHODS: 119 patients with hypomyelinating disorders in Chinese population were enrolled and evaluated based on their history, clinical manifestation, laboratory examinations, series of brain MRI with follow-up, genetic etiological tests including chromosomal analysis, multiplex ligation probe amplification, Sanger sequencing, targeted enrichment-based next-generation sequencing and whole exome sequencing...
2018: PloS One
https://www.readbyqxmd.com/read/29451301/intu-related-oral-facial-digital-syndrome-type-vi-a-confirmatory-report
#16
A-L Bruel, J Levy, N Elenga, A Defo, A Favre, H Lucron, Y Capri, L Perrin, S Passemard, Y Vial, A-C Tabet, L Faivre, C Thauvin-Robinet, A Verloes
Oral-facial-digital (OFD) syndromes are a subgroup of ciliopathies distinguished by the co-occurrence of hamartomas and/or multiple frenula of the oral region and digital anomalies. Several clinical forms of OFD are distinguished by their associated anomalies and/or inheritance patterns, and at least 20 genetic types of OFD have been delineated. We describe here a child with preaxial and postaxial polydactyly, lingual hamartoma, a congenital heart defect, delayed development and cerebellar peduncles displaying the molar tooth sign...
February 16, 2018: Clinical Genetics
https://www.readbyqxmd.com/read/29450879/genetic-investigation-of-93-families-with-microphthalmia-or-posterior-microphthalmos
#17
N Patel, A O Khan, S Alsahli, G Abdel-Salam, S R Nowilaty, A M Mansour, A Nabil, M Al-Owain, S Sogati, M A Salih, A M Kamal, H Alsharif, H Alsaif, S S Alzahrani, F Abdulwahab, N Ibrahim, M Hashem, T Faquih, Z A Shah, M Abouelhoda, D Monies, M Dasouki, R Shaheen, S Majid, M A Aldahmesh, F S Alkuraya
Microphthalmia is a developmental eye defect that is highly variable in severity and in its potential for systemic association. Despite the discovery of many disease genes in microphthalmia, at least 50% of patients remain undiagnosed genetically. Here, we describe a cohort of 147 patients (93 families) from our highly consanguineous population with various forms of microphthalmia (including the distinct entity of posterior microphthalmos) that were investigated using a next-generation sequencing multi-gene panel (i-panel) as well as whole exome sequencing (WES) and molecular karyotyping...
February 16, 2018: Clinical Genetics
https://www.readbyqxmd.com/read/29449720/biallelic-inactivating-variants-in-the-gtpbp2-gene-cause-a-neurodevelopmental-disorder-with-severe-intellectual-disability
#18
Aida M Bertoli-Avella, Jose M Garcia-Aznar, Oliver Brandau, Fahad Al-Hakami, Zafer Yüksel, Anett Marais, Nana-Maria Grüning, Lia Abbasi Moheb, Omid Paknia, Nahla Alshaikh, Seham Alameer, Makia J Marafi, Fahd Al-Mulla, Nouriya Al-Sannaa, Arndt Rolfs, Peter Bauer
Congenital neurological disorders are genetically highly heterogeneous. Rare forms of hereditary neurological disorders are still difficult to be adequately diagnosed. Pertinent studies, especially when reporting only single families, need independent confirmation. We present three unrelated families in which whole-exome sequencing identified the homozygous non-sense variants c.430[C>T];[C>T] p.(Arg144*), c.1219[C>T];[C>T] p.(Gln407*) and c.1408[C>T];[C>T] p.(Arg470*) in GTPBP2. Their clinical presentations include early onset and apparently non-progressive motor and cognitive impairment, and thereby overlap with findings in a recently described family harbouring a homozygous GTPBP2 splice site variant...
February 15, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29449551/mutations-in-cfap43-and-cfap44-cause-male-infertility-and-flagellum-defects-in-trypanosoma-and-human
#19
Charles Coutton, Alexandra S Vargas, Amir Amiri-Yekta, Zine-Eddine Kherraf, Selima Fourati Ben Mustapha, Pauline Le Tanno, Clémentine Wambergue-Legrand, Thomas Karaouzène, Guillaume Martinez, Serge Crouzy, Abbas Daneshipour, Seyedeh Hanieh Hosseini, Valérie Mitchell, Lazhar Halouani, Ouafi Marrakchi, Mounir Makni, Habib Latrous, Mahmoud Kharouf, Jean-François Deleuze, Anne Boland, Sylviane Hennebicq, Véronique Satre, Pierre-Simon Jouk, Nicolas Thierry-Mieg, Beatrice Conne, Denis Dacheux, Nicolas Landrein, Alain Schmitt, Laurence Stouvenel, Patrick Lorès, Elma El Khouri, Serge P Bottari, Julien Fauré, Jean-Philippe Wolf, Karin Pernet-Gallay, Jessica Escoffier, Hamid Gourabi, Derrick R Robinson, Serge Nef, Emmanuel Dulioust, Raoudha Zouari, Mélanie Bonhivers, Aminata Touré, Christophe Arnoult, Pierre F Ray
Spermatogenesis defects concern millions of men worldwide, yet the vast majority remains undiagnosed. Here we report men with primary infertility due to multiple morphological abnormalities of the sperm flagella with severe disorganization of the sperm axoneme, a microtubule-based structure highly conserved throughout evolution. Whole-exome sequencing was performed on 78 patients allowing the identification of 22 men with bi-allelic mutations in DNAH1 (n = 6), CFAP43 (n = 10), and CFAP44 (n = 6). CRISPR/Cas9 created homozygous CFAP43/44 male mice that were infertile and presented severe flagellar defects confirming the human genetic results...
February 15, 2018: Nature Communications
https://www.readbyqxmd.com/read/29449315/metaplastic-breast-cancer-in-a-patient-with-neurofibromatosis-type-1-and-somatic-loss-of-heterozygosity
#20
Lorena Suarez-Kelly, Keiko Akagi, Julie W Reeser, Eric Samorodnitsky, Matthew Reeder, Amy Smith, Sameek Roychowdhury, David E Symer, William E Carson
Metaplastic breast carcinoma (MBC) is rare and has a poor prognosis. Here we describe genetic analysis of a 41-year-old female patient with MBC and neurofibromatosis type I (NF1). She initially presented with pT3N1a, grade 3 MBC, but lung metastases were discovered subsequently. To identify the molecular cause of her NF1, we screened for germline mutations disrupting NF1 or SPRED1, revealing a heterozygous germline single nucleotide variant (SNV) in exon 21 of NF1 at c.2709G>A, chr17: 29556342. By report, this variant disrupts pre-mRNA splicing of NF1 transcripts...
February 15, 2018: Cold Spring Harbor Molecular Case Studies
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