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Copy-number variant

Kari Branham, Hiroko Matsui, Pooja Biswas, Aditya A Guru, Michael Hicks, John J Suk, He Li, David Jakubosky, Tao Long, Amalio Telenti, Naoki Narai, John R Heckenlively, Kelly A Frazar, Paul A Sieving, Radha Ayyagari
While more than 250 genes are known to cause inherited retinal degenerations (IRD), nearly 40-50% of families have the genetic basis for their disease unknown. In this study we sought to identify the underlying cause of inherited retinal degeneration (IRD) in a family by whole genome sequence (WGS) analysis. Clinical characterization including standard ophthalmic examination, fundus photography, visual field testing, electroretinography, and review of medical and family history was performed. WGS was performed on affected and unaffected family members using Illumina HiSeq X10...
October 7, 2016: Physiological Genomics
Gilles Maussion, Cristiana Cruceanu, Jill A Rosenfeld, Scott C Bell, Fabrice Jollant, Jin Szatkiewicz, Ryan L Collins, Carrie Hanscom, Ilaria Kolobova, Nicolas Menjot de Champfleur, Ian Blumenthal, Colby Chiang, Vanessa Ota, Christina Hultman, Colm O'Dushlaine, Steve McCarroll, Martin Alda, Sebastien Jacquemont, Zehra Ordulu, Christian R Marshall, Melissa T Carter, Lisa G Shaffer, Pamela Sklar, Santhosh Girirajan, Cynthia C Morton, James F Gusella, Gustavo Turecki, Dimitri J Stavropoulos, Patrick F Sullivan, Stephen W Scherer, Michael E Talkowski, Carl Ernst
We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11...
October 19, 2016: American Journal of Medical Genetics. Part A
William J Gammerdinger, Matthew A Conte, Jean-François Baroiller, Helena D'Cotta, Thomas D Kocher
BACKGROUND: Inversions and other structural polymorphisms often reduce the rate of recombination between sex chromosomes, making it impossible to fine map sex-determination loci using traditional genetic mapping techniques. Here we compare distantly related species of tilapia that each segregate an XY system of sex-determination on linkage group 1. We use whole genome sequencing to identify shared sex-patterned polymorphisms, which are candidates for the ancestral sex-determination mutation...
October 18, 2016: BMC Genomics
Zachery R Reichert, Maha Hussain
The development of metastatic castration-resistant prostate cancer (mCRPC) signals the terminal disease phase. The preceding hormone-dependent disease setting is effectively managed with androgen deprivation therapy. This foundation of treatment has a high rate of biochemical and clinical response and meaningful clinical benefit but is finite in duration as most cancers will progress to castration resistance. Historically, treatment for mCRPC entailed androgen receptor (AR) inhibitors (nilutamide, flutamide, bicalutamide), nonspecific steroidal biosynthesis inhibitors (ketoconazole, itraconazole), steroids (prednisone, diethylstilbesterol, dexamethasone), or palliative chemotherapy (mitoxantrone, estramustine), but none of these strategies impacted survival...
September 2016: Cancer Journal
Beryl Royer-Bertrand, Matteo Torsello, Donata Rimoldi, Ikram El Zaoui, Katarina Cisarova, Rosanna Pescini-Gobert, Franck Raynaud, Leonidas Zografos, Ann Schalenbourg, Daniel Speiser, Michael Nicolas, Laureen Vallat, Robert Klein, Serge Leyvraz, Giovanni Ciriello, Nicolò Riggi, Alexandre P Moulin, Carlo Rivolta
Uveal melanoma (UM) is a rare intraocular tumor that, similar to cutaneous melanoma, originates from melanocytes. To gain insights into its genetics, we performed whole-genome sequencing at very deep coverage of tumor-control pairs in 33 samples (24 primary and 9 metastases). Genome-wide, the number of coding mutations was rather low (only 17 variants per tumor on average; range 7-28), thus radically different from cutaneous melanoma, where hundreds of exonic DNA insults are usually detected. Furthermore, no UV light-induced mutational signature was identified...
October 6, 2016: American Journal of Human Genetics
Mayuko Furuta, Masaki Ueno, Akihiro Fujimoto, Shinya Hayami, Satoru Yasukawa, Fumiyoshi Kojima, Koji Arihiro, Yoshiiku Kawakami, Christopher P Wardell, Yuichi Shiraishi, Hiroko Tanaka, Kaoru Nakano, Kazuhiro Maejima, Aya Sasaki-Oku, Naoki Tokunaga, Keith A Boroevich, Tetsuo Abe, Hiroshi Aikata, Hideki Ohdan, Kunihito Goto, Michiaki Kubo, Tatsuhiko Tsunoda, Satoru Miyano, Kazuaki Chayama, Hiroki Yamaue, Hidewaki Nakagawa
BACKGROUND & AIMS: Liver cancer has a high risk of multi-centric (MC) occurrence due to a strong carcinogenic background in the liver, in addition to a high risk of intrahepatic metastasis (IM). There are large characteristic differences between IM and MC with regards to their development and clinical outcome, but discriminating between IM and MC is usually non-trivial with respect to clinical or pathological aspects. METHODS: In this study, we performed whole-genome and RNA sequencing analyses of 49 liver nodules and two extra-hepatic metastatic tumors from 23 patients to investigate for any potential to discriminate between IM and MC at the molecular level...
October 11, 2016: Journal of Hepatology
Peilin Jia, Guangchun Han, Junfei Zhao, Pinyi Lu, Zhongming Zhao
SZGR 2.0 is a comprehensive resource of candidate variants and genes for schizophrenia, covering genetic, epigenetic, transcriptomic, translational and many other types of evidence. By systematic review and curation of multiple lines of evidence, we included almost all variants and genes that have ever been reported to be associated with schizophrenia. In particular, we collected ∼4200 common variants reported in genome-wide association studies, ∼1000 de novo mutations discovered by large-scale sequencing of family samples, 215 genes spanning rare and replication copy number variations, 99 genes overlapping with linkage regions, 240 differentially expressed genes, 4651 differentially methylated genes and 49 genes as antipsychotic drug targets...
October 12, 2016: Nucleic Acids Research
Evert van den Broek, Oscar Krijgsman, Daoud Sie, Marianne Tijssen, Sandra Mongera, Mark A van de Wiel, Eric J. Belt, Sjoerd H den Uil, Herman Bril, Hein B A C Stockmann, Bauke Ylstra, Beatriz Carvalho, Gerrit A Meijer, Remond J A Fijneman
Tumor profiling of DNA alterations, i.e. gene point mutations, somatic copy number aberrations (CNAs) and structural variants (SVs), improves insight into the molecular pathology of cancer and clinical outcome. Here, associations between genomic aberrations and disease recurrence in stage II and III colon cancers were investigated. A series of 114 stage II and III microsatellite stable colon cancer samples were analyzed by high-resolution array-comparative genomic hybridization (array-CGH) to detect CNAs and CNA-associated chromosomal breakpoints (SVs)...
October 6, 2016: Oncotarget
S A Forbes, D Beare, N Bindal, S Bamford, S Ward, C G Cole, M Jia, C Kok, H Boutselakis, T De, Z Sondka, L Ponting, R Stefancsik, B Harsha, J Tate, E Dawson, S Thompson, H Jubb, P J Campbell
COSMIC ( is an expert-curated database of somatic mutations in human cancer. Broad and comprehensive in scope, recent releases in 2016 describe over 4 million coding mutations across all human cancer disease types. Mutations are annotated across the entire genome, but expert curation is focused on over 400 key cancer genes. Now encompassing the majority of molecular mutation mechanisms in oncogenetics, COSMIC additionally describes 10 million non-coding mutations, 1 million copy-number aberrations, 9 million gene-expression variants, and almost 8 million differentially methylated CpGs...
October 11, 2016: Current Protocols in Human Genetics
P Pasanen, J Mäkinen, L Myllykangas, R Guerreiro, J Bras, M Valori, M Viitanen, M Baumann, P J Tienari, M Pöyhönen, P Baumann
OBJECTIVES: Primary familial brain calcification (PFBC) is a rare neurological disease often inherited as a dominant trait. Mutations in four genes (SLC20A2, PDGFB, PDGFRB, and XPR1) have been reported in patients with PFBC. Of these, point mutations or small deletions in SLC20A2 are most common. Thus far, only one large deletion covering entire SLC20A2 and several smaller, exonic deletions of SLC20A2 have been reported. The aim of this study was to identify the causative gene defect in a Finnish PFBC family with three affected patients...
October 10, 2016: Acta Neurologica Scandinavica
Tibor Vaszkó, János Papp, Csilla Krausz, Elena Casamonti, Lajos Géczi, Edith Olah
Due to its palindromic setup, AZFc (Azoospermia Factor c) region of chromosome Y is one of the most unstable regions of the human genome. It contains eight gene families expressed mainly in the testes. Several types of rearrangement resulting in changes in the cumulative copy number of the gene families were reported to be associated with diseases such as male infertility and testicular germ cell tumors. The best studied AZFc rearrangement is gr/gr deletion. Its carriers show widespread phenotypic variation from azoospermia to normospermia...
2016: PloS One
Leila Sabour, Maryam Sabour, Saeid Ghorbian
With the advancement and improvement of new sequencing technology, next-generation sequencing (NGS) has been applied increasingly in cancer genomics research fields. More recently, NGS has been adopted in clinical oncology to advance personalized treatment of cancer. NGS is utilized to novel diagnostic and rare cancer mutations, detection of translocations, inversions, insertions and deletions, detection of copy number variants, detect familial cancer mutation carriers, provide the molecular rationale for appropriate targeted, therapeutic and prognostic...
October 8, 2016: Pathology Oncology Research: POR
Laura Valle
The development of genome-wide massively parallel sequencing, i.e. whole-genome and whole-exome sequencing, and copy number approaches had raised high expectations for the identification of novel hereditary colorectal cancer genes. Although relatively successful for genes causing adenomatous polyposis syndromes, both autosomal dominant and recessive, the identification of genes associated with hereditary non-polyposis colorectal cancer has proven extremely challenging, mainly due to the absence of major high penetrance genes and the difficulty in demonstrating the functional impact of the identified variants and their causal association with tumor development...
October 3, 2016: Clinical Gastroenterology and Hepatology
Ferdouse Begum, Ingo Ruczinski, John E Hokanson, Sharon M Lutz, Margaret M Parker, Michael H Cho, Jacqueline B Hetmanski, Robert B Scharpf, James D Crapo, Edwin K Silverman, Terri H Beaty
Many well-powered genome-wide association studies have identified genetic determinants of self-reported smoking behaviors and measures of nicotine dependence, but most have not considered the role of structural variants, such as copy number variation (CNVs), influencing these phenotypes. Here, we included 2,889 African American and 6,187 non-Hispanic White subjects from the COPDGene cohort ( to carefully investigate the role of polymorphic CNVs across the genome on various measures of smoking behavior...
2016: PloS One
Boas Pucker, Daniela Holtgräwe, Thomas Rosleff Sörensen, Ralf Stracke, Prisca Viehöver, Bernd Weisshaar
Arabidopsis thaliana is the most important model organism for fundamental plant biology. The genome diversity of different accessions of this species has been intensively studied, for example in the 1001 genome project which led to the identification of many small nucleotide polymorphisms (SNPs) and small insertions and deletions (InDels). In addition, presence/absence variation (PAV), copy number variation (CNV) and mobile genetic elements contribute to genomic differences between A. thaliana accessions. To address larger genome rearrangements between the A...
2016: PloS One
Gamou Fall, Martin Faye, Manfred Weidmann, Marco Kaiser, Anne Dupressoir, El Hadj Ndiaye, Yamar Ba, Mawlouth Diallo, Ousmane Faye, Amadou Alpha Sall
West Nile virus (WNV) is an emerging arbovirus, circulating worldwide between birds and mosquitoes, which impacts human and animal health. Since the mid-1990s, WNV outbreaks have emerged in Europe and America and represent currently the primary cause of encephalitis in the United States. WNV exhibits a great genetic diversity with at least eight different lineages circulating in the world, and four (1, 2, Koutango, and putative new) are present in Africa. These different WNV lineages are not readily differentiated by serology, and thus, rapid molecular tools are required for diagnostic...
October 6, 2016: Vector Borne and Zoonotic Diseases
Jana Sochorová, Olivier Coriton, Alena Kuderová, Jana Lunerová, Anne-Marie Chèvre, Aleš Kovařík
BACKGROUND AND AIMS: Brassica napus (AACC, 2n = 38, oilseed rape) is a relatively recent allotetraploid species derived from the putative progenitor diploid species Brassica rapa (AA, 2n = 20) and Brassica oleracea (CC, 2n = 18). To determine the influence of intensive breeding conditions on the evolution of its genome, we analysed structure and copy number of rDNA in 21 cultivars of B. napus, representative of genetic diversity. METHODS: We used next-generation sequencing genomic approaches, Southern blot hybridization, expression analysis and fluorescence in situ hybridization (FISH)...
October 5, 2016: Annals of Botany
Saliha Hammoumi, Tatiana Vallaeys, Ayi Santika, Philippe Leleux, Ewa Borzym, Christophe Klopp, Jean-Christophe Avarre
Koi herpesvirus disease (KHVD) is an emerging disease that causes mass mortality in koi and common carp, Cyprinus carpio L. Its causative agent is Cyprinid herpesvirus 3 (CyHV-3), also known as koi herpesvirus (KHV). Although data on the pathogenesis of this deadly virus is relatively abundant in the literature, still little is known about its genomic diversity and about the molecular mechanisms that lead to such a high virulence. In this context, we developed a new strategy for sequencing full-length CyHV-3 genomes directly from infected fish tissues...
2016: PeerJ
Salomon Manier, Karma Salem, Siobhan V Glavey, Aldo M Roccaro, Irene M Ghobrial
Multiple myeloma (MM) is a genetically complex disease. The past few years have seen an evolution in cancer research with the emergence of next-generation sequencing (NGS), enabling high throughput sequencing of tumors-including whole exome, whole genome, RNA, and single-cell sequencing as well as genome-wide association study (GWAS). A few inherited variants have been described, counting for some cases of familial disease. Hierarchically, primary events in MM can be divided into hyperdiploid (HDR) and nonhyperdiploid subtypes...
2016: Cancer Treatment and Research
Andrea Ganna, Giulio Genovese, Daniel P Howrigan, Andrea Byrnes, Mitja I Kurki, Seyedeh M Zekavat, Christopher W Whelan, Mart Kals, Michel G Nivard, Alex Bloemendal, Jonathan M Bloom, Jacqueline I Goldstein, Timothy Poterba, Cotton Seed, Robert E Handsaker, Pradeep Natarajan, Reedik Mägi, Diane Gage, Elise B Robinson, Andres Metspalu, Veikko Salomaa, Jaana Suvisaari, Shaun M Purcell, Pamela Sklar, Sekar Kathiresan, Mark J Daly, Steven A McCarroll, Patrick F Sullivan, Aarno Palotie, Tõnu Esko, Christina M Hultman, Benjamin M Neale
Disruptive, damaging ultra-rare variants in highly constrained genes are enriched in individuals with neurodevelopmental disorders. In the general population, this class of variants was associated with a decrease in years of education (YOE). This effect was stronger among highly brain-expressed genes and explained more YOE variance than pathogenic copy number variation but less than common variants. Disruptive, damaging ultra-rare variants in highly constrained genes influence the determinants of YOE in the general population...
October 3, 2016: Nature Neuroscience
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