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https://www.readbyqxmd.com/read/28427458/whole-exome-sequencing-identifies-novel-candidate-predisposition-genes-for-familial-polycythemia-vera
#1
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
#2
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...
April 1, 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
#3
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
#4
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
#5
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
#6
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 (NTDs), 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 re-sequencing analysis of GRHL3 in a cohort of 233 familial and sporadic cases of spina bifida...
March 8, 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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
https://www.readbyqxmd.com/read/28137713/hipred-an-integrative-approach-to-predicting-haploinsufficient-genes
#14
Hashem A Shihab, Mark F Rogers, Colin Campbell, Tom R Gaunt
MOTIVATION: A major cause of autosomal dominant disease is haploinsufficiency, whereby a single copy of a gene is not sufficient to maintain the normal function of the gene. A large proportion of existing methods for predicting haploinsufficiency incorporate biological networks, e.g. protein-protein interaction networks, that have recently been shown to introduce study bias. As a result, these methods tend to perform best on well studied genes, but underperform on less studied genes. The advent of large genome sequencing consortia, such as the 1,000 genomes project, NHLBI Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC) creates an urgent need for unbiased haploinsufficiency prediction methods...
January 30, 2017: Bioinformatics
https://www.readbyqxmd.com/read/28118812/a-practical-guide-to-filtering-and-prioritizing-genetic-variants
#15
Mahjoubeh Jalali Sefid Dashti, Junaid Gamieldien
Next-generation sequencing (NGS) of whole genomes and exomes is a powerful tool in biomedical research and clinical diagnostics. However, the vast amount of data produced by NGS introduces new challenges and opportunities, many of which require novel computational and theoretical approaches when it comes to identifying the causal variant(s) for a disease of interest. While workflows and associated software to process raw data and produce high-confidence variant calls have significantly improved, filtering tens of thousands of candidates to identify a subset relevant to a specific study is still a complex exercise best left to bioinformaticists...
January 1, 2017: BioTechniques
https://www.readbyqxmd.com/read/28093075/gavin-gene-aware-variant-interpretation-for-medical-sequencing
#16
K Joeri van der Velde, Eddy N de Boer, Cleo C van Diemen, Birgit Sikkema-Raddatz, Kristin M Abbott, Alain Knopperts, Lude Franke, Rolf H Sijmons, Tom J de Koning, Cisca Wijmenga, Richard J Sinke, Morris A Swertz
We present Gene-Aware Variant INterpretation (GAVIN), a new method that accurately classifies variants for clinical diagnostic purposes. Classifications are based on gene-specific calibrations of allele frequencies from the ExAC database, likely variant impact using SnpEff, and estimated deleteriousness based on CADD scores for >3000 genes. In a benchmark on 18 clinical gene sets, we achieve a sensitivity of 91.4% and a specificity of 76.9%. This accuracy is unmatched by 12 other tools. We provide GAVIN as an online MOLGENIS service to annotate VCF files and as an open source executable for use in bioinformatic pipelines...
January 16, 2017: Genome Biology
https://www.readbyqxmd.com/read/28073829/dutpase-dut-is-mutated-in-a-novel-monogenic-syndrome-with-diabetes-and-bone-marrow-failure
#17
Reinaldo Sousa Dos Santos, Mathilde Daures, Anne Philippi, Sophie Romero, Lorella Marselli, Piero Marchetti, Valérie Senée, Delphine Bacq, Céline Besse, Baz Baz, Laura Marroquí, Sarah Ivanoff, Julien Masliah-Planchon, Marc Nicolino, Jean Soulier, Gérard Socié, Decio L Eizirik, Jean-François Gautier, Cécile Julier
We describe a new syndrome characterized by early-onset diabetes associated with bone marrow failure, affecting mostly the erythrocytic lineage. Using whole-exome sequencing in a remotely consanguineous patient from a family with two affected siblings, we identified a single homozygous missense mutation (chr15.hg19:g.48,626,619A>G) located in the dUTPase (DUT) gene (National Center for Biotechnology Information Gene ID 1854), affecting both the mitochondrial (DUT-M p.Y142C) and the nuclear (DUT-N p.Y54C) isoforms...
April 2017: Diabetes
https://www.readbyqxmd.com/read/28062663/a-population-based-analysis-of-germline-bap1-mutations-in-melanoma
#18
Sally J O'Shea, Carla Daniela Robles-Espinoza, Lauren McLellan, Jeanine Harrigan, Xavier Jacq, James Hewinson, Vivek Iyer, Will Merchant, Faye Elliott, Mark Harland, D Timothy Bishop, Julia Newton-Bishop, David J Adams
Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found...
January 5, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28053047/structural-analysis-of-pathogenic-mutations-in-the-dyrk1a-gene-in-patients-with-developmental-disorders
#19
Jochem M G Evers, Roman A Laskowski, Marta Bertolli, Jill Clayton-Smith, Charu Deshpande, Jacqueline Eason, Frances Elmslie, Frances Flinter, Carol Gardiner, Jane A Hurst, Helen Kingston, Usha Kini, Anne K Lampe, Derek Lim, Alison Male, Swati Naik, Michael J Parker, Sue Price, Leema Robert, Ajoy Sarkar, Volker Straub, Geoff Woods, Janet M Thornton, Caroline F Wright
Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is currently unclear. Here we present 19 de novo mutations in this gene, including five missense mutations, identified by the Deciphering Developmental Disorder study. Protein structural analysis reveals that the missense mutations are either close to the ATP or peptide binding-sites within the kinase domain, or are important for protein stability, suggesting they lead to a loss of the protein's function mechanism...
February 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28018608/digenic-mutations-of-human-ocrl-paralogs-in-dent-s-disease-type-2-associated-with-chiari-i-malformation
#20
Daniel Duran, Sheng Chih Jin, Tyrone DeSpenza, Carol Nelson-Williams, Andrea G Cogal, Elizabeth W Abrash, Peter C Harris, John C Lieske, Serena Je Shimshak, Shrikant Mane, Kaya Bilguvar, Michael L DiLuna, Murat Günel, Richard P Lifton, Kristopher T Kahle
OCRL1 and its paralog INPP5B encode phosphatidylinositol 5-phosphatases that localize to the primary cilium and have roles in ciliogenesis. Mutations in OCRL1 cause the X-linked Dent disease type 2 (DD2; OMIM# 300555), characterized by low-molecular weight proteinuria, hypercalciuria, and the variable presence of cataracts, glaucoma and intellectual disability without structural brain anomalies. Disease-causing mutations in INPP5B have not been described in humans. Here, we report the case of an 11-year-old boy with short stature and an above-average IQ; severe proteinuria, hypercalciuria and osteopenia resulting in a vertebral compression fracture; and Chiari I malformation with cervico-thoracic syringohydromyelia requiring suboccipital decompression...
2016: Human Genome Variation
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