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Copy-number variant

Christian R Wewer, Himanshu Khandelia
The flavivirus Zika virus (ZV) became an international emergency within two years of its outbreak in the Americas. Dengue virus (DENV), which is also a flavivirus, causes significant clinical harm in equatorial regions. A common feature amongst flaviviruses like ZV and DENV is an icosahedral shell of exactly 180 copies of the envelope (E) and membrane (M) proteins anchored in a lipid membrane, which engulfs the viral RNA and capsid proteins. Host recognition by both ZV and DENV is linked to the presence of phosphatidylserine (PS) and phosphatidylethanolamine (PE) lipids in the viral lipidome...
June 22, 2018: Soft Matter
Peilin Jia, Xiangning Chen, Wei Xie, Kenneth S Kendler, Zhongming Zhao
Numerous high-throughput omics studies have been conducted in schizophrenia, providing an accumulated catalog of susceptible variants and genes. The results from these studies, however, are highly heterogeneous. The variants and genes nominated by different omics studies often have limited overlap with each other. There is thus a pressing need for integrative analysis to unify the different types of data and provide a convergent view of schizophrenia candidate genes (SZgenes). In this study, we collected a comprehensive, multidimensional dataset, including 7819 brain-expressed genes...
June 20, 2018: Schizophrenia Bulletin
Danijela Krgovic, Nadja Kokalj Vokac, Andreja Zagorac, Hojka Gregoric Kumperscak
Detection of copy number variations (CNVs) is a first-tier clinical diagnostic test for children with neurodevelopmental disorders (NDD), which reveals the genetic cause of the disorder in more than 20%. These are mostly known microdeletion/microduplication syndromes, but variants of unknown clinical significance (VOUS) and ambiguous CNVs can also be detected. An example of the last two are abnormalities in the DOCK8 gene. Conflicting interpretations of CNVs affecting DOCK8 can be found in the literature. Deletions were predicted to have a impact in carriers with variable clinical manifestations, where duplications have been proposed as benign variants...
June 21, 2018: Scientific Reports
Leda Coelewij, David Curtis
A number of important findings have recently emerged relevant to identifying genetic risk factors for schizophrenia. Findings using common variants point towards gene sets of interest and also demonstrate an overlap with other psychiatric and nonpsychiatric disorders. Imputation of variants of the gene for complement component 4 (C4) from GWAS data has shown that the predicted expression of the C4A product is associated with schizophrenia risk. Very rare variants disrupting SETD1A, RBM12 or NRXN1 have a large effect on risk...
June 20, 2018: Annals of Human Genetics
Xu Zhang, Yuzhuo Wang, Tian Tian, Gangqiao Zhou, Guangfu Jin
Genome-wide association studies have identified several germline variants in gastric cancer. Meanwhile, sequencing studies have characterized extensive somatic alterations that arise during gastric carcinogenesis. However, the relationship between the germline variants and somatic alterations is still unclear in gastric cancer. A total of 11 susceptibility loci and 276 driver genes of gastric cancer were determined based on previous studies and publicly available database. An enrichment analysis was made to detect whether driver genes were enriched in susceptibility regions...
June 20, 2018: Cancer Medicine
Venugopal S Vineeth, Usha R Dutta, Karthik Tallapakka, Aneek Das Bhowmik, Ashwin Dalal
Rett syndrome is a neurodevelopmental disorder affecting the nervous, musculoskeletal and gastroenteric systems. Affected individuals show normal neonatal development for 6-18 months followed by sudden growth arrest, psychomotor retardation and a broad spectrum of clinical features. Sequence variants in MECP2 gene have been identified as the major genetic etiology accounting for 90-95% of patients. Apart from MECP2, pathogenic sequence variants and copy number variants of FOXG1 gene lead to congenital type of Rett syndrome which is a more severe form and characterised by absence of early normal development as seen in classical Rett syndrome...
June 16, 2018: Gene
Katya Mokretar, Daniel Pease, Jan-Willem Taanman, Aynur Soenmez, Ayesha Ejaz, Tammaryn Lashley, Helen Ling, Steve Gentleman, Henry Houlden, Janice L Holton, Anthony H V Schapira, Elizabeth Nacheva, Christos Proukakis
The α-synuclein protein, encoded by SNCA, has a key role in the pathogenesis of Parkinson's disease and other synucleinopathies. Although usually sporadic, Parkinson's disease can result from inherited copy number variants in SNCA and other genes. We have hypothesized a role of somatic SNCA mutations, leading to mosaicism, in sporadic synucleinopathies. The evidence for mosaicism in healthy and diseased brain is increasing rapidly, with somatic copy number gains of APP reported in Alzheimer's brain. Here we demonstrate somatic SNCA copy number gains in synucleinopathies (Parkinson's disease and multiple system atrophy), focusing on substantia nigra...
June 15, 2018: Brain: a Journal of Neurology
Sandro Marini, William J Devan, Farid Radmanesh, Laura Miyares, Timothy Poterba, Björn M Hansen, Bo Norrving, Jordi Jimenez-Conde, Eva Giralt-Steinhauer, Roberto Elosua, Elisa Cuadrado-Godia, Carolina Soriano, Jaume Roquer, Christina E Kourkoulis, Alison M Ayres, Kristin Schwab, David L Tirschwell, Magdy Selim, Devin L Brown, Scott L Silliman, Bradford B Worrall, James F Meschia, Chelsea S Kidwell, Joan Montaner, Israel Fernandez-Cadenas, Pilar Delgado, Steven M Greenberg, Arne Lindgren, Charles Matouk, Kevin N Sheth, Daniel Woo, Christopher D Anderson, Jonathan Rosand, Guido J Falcone
BACKGROUND AND PURPOSE: Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. METHODS: We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry...
June 18, 2018: Stroke; a Journal of Cerebral Circulation
Eline Overwater, Luisa Marsili, Marieke J H Baars, Annette F Baas, Irma van de Beek, Eelco Dulfer, Johanna M van Hagen, Yvonne Hilhorst-Hofstee, Marlies Kempers, Ingrid P Krapels, Leonie A Menke, Judith M A Verhagen, Kak K Yeung, Petra J G Zwijnenburg, Maarten Groenink, Peter van Rijn, Marjan M Weiss, Els Voorhoeve, J Peter van Tintelen, Arjan C Houweling, Alessandra Maugeri
Simultaneous analysis of multiple genes using next generation sequencing (NGS) technology has become widely available. Copy number variations (CNVs) in disease-associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H-TAD) associated genes. 810 patients suspected of H-TAD were analysed by targeted NGS analysis of 21 H-TAD associated genes...
June 16, 2018: Human Mutation
Kai Lee Yap, Amy E Knight Johnson, David Fischer, Priscilla Kandikatla, Jacea Deml, Viswateja Nelakuditi, Sara Halbach, George S Jeha, Lindsay C Burrage, Olaf Bodamer, Valeria C Benavides, Andrea M Lewis, Sian Ellard, Pratik Shah, Declan Cody, Alejandro Diaz, Aishwarya Devarajan, Lisa Truong, Siri Atma W Greeley, Diva D De Leó-Crutchlow, Andrew C Edmondson, Soma Das, Paul Thornton, Darrel Waggoner, Daniela Del Gaudio
PURPOSE: Describe the clinical and molecular findings of patients with Kabuki syndrome (KS) who present with hypoglycemia due to congenital hyperinsulinism (HI), and assess the incidence of KS in patients with HI. METHODS: We documented the clinical features and molecular diagnoses of 10 infants with persistent HI and KS via a combination of sequencing and copy-number profiling methodologies. Subsequently, we retrospectively evaluated 100 infants with HI lacking a genetic diagnosis, for causative variants in KS genes...
June 15, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Xiaofei Song, Christine R Beck, Renqian Du, Ian M Campbell, Zeynep Coban-Akdemir, Shen Gu, Amy M Breman, Pawel Stankiewicz, Grzegorz Ira, Chad A Shaw, James R Lupski
Alu elements, the short interspersed element numbering >1 million copies per human genome, can mediate the formation of copy number variants (CNVs) between substrate pairs. These Alu/Alu-mediated rearrangements (AAMR) can result in pathogenic variants that cause diseases. To investigate the impact of AAMR on gene variation and human health, we first characterized Alus that are involved in mediating CNVs (CNV-Alus) and observed that these Alus tend to be evolutionarily younger. We then computationally generated, with the assistance of a supercomputer, a test dataset consisting of 78 million Alu pairs and predicted ~18% of them are potentially susceptible to AAMR...
June 15, 2018: Genome Research
Alexandra S Whale, Gerwyn M Jones, Jernej Pavšič, Tanja Dreo, Nicholas Redshaw, Sema Akyurek, Muslum Akgoz, Carla Divieto, Maria PaolaSassi, Hua-Jun He, Kenneth D Cole, Young-Kyung Bae, Sang-Ryoul Park, Liesbet Deprez, Philippe Corbisier, Sonia Garrigou, Valérie Taly, Raquel Larios, Simon Cowen, Denise M O'Sullivan, Claire A Bushell, Heidi Goenaga-Infante, Carole A Foy, Alison J Woolford, Helen Parkes, Jim F Huggett, Alison S Devonshire
BACKGROUND: Genetic testing of tumor tissue and circulating cell-free DNA for somatic variants guides patient treatment of many cancers. Such measurements will be fundamental in the future support of precision medicine. However, there are currently no primary reference measurement procedures available for nucleic acid quantification that would support translation of tests for circulating tumor DNA into routine use. METHODS: We assessed the accuracy of digital PCR (dPCR) for copy number quantification of a frequently occurring single-nucleotide variant in colorectal cancer ( KRAS c...
June 14, 2018: Clinical Chemistry
Enza Maria Valente, Sara Nuovo, Dan Doherty
The approach to identifying a genetic cause in patients with cerebellar disorders relies on history, examination, consultation, and testing, combined with specialized expertise because they are rare and genetically diverse. Cerebellar disorders can be caused by a variety of DNA alterations including single-nucleotide changes, small insertions or deletions, larger copy number variants, and nucleotide repeat expansions, exhibiting autosomal-recessive, autosomal-dominant (inherited and de novo), X-linked, and mitochondrial modes of inheritance...
2018: Handbook of Clinical Neurology
Xiaojia Xu, Yulian Li, Yaping Liang, Mingjuan Yin, Yan Zhang, Lingfeng Huang, Zuwei Yu, Jindong Ni
It is known that multiple genetic variants can affect immune responses to the hepatitis B virus (HBV) vaccine. A case-control study was undertaken to examine the possible association of low responsiveness to the HBV vaccine in a Chinese population with genetic polymorphisms in integrin subunit alpha L, CD58, tumor necrosis factor superfamily member 15, C-C motif chemokine ligand 15, transforming growth factor beta 3, and B-cell lymphoma 6 protein. The copy numbers of these six genes were detected in 129 low responders, 129 middle responders and 129 high responders to HBV vaccination...
June 11, 2018: Infection, Genetics and Evolution
Andreas Syrimis, Nayia Nicolaou, Angelos Alexandrou, Ioannis Papaevripidou, Michael Nicolaou, Eleni Loukianou, Carolina Sismani, Stavros Malas, Violetta Christophidou-Anastasiadou, George A Tanteles
The present study investigated the clinical and mutational spectrum of aniridia in a cohort of 17 affected individuals from six families from Cyprus. Each proband was initially evaluated for copy number variants at the PAX6 locus and subsequently underwent PAX6 mutation screening. Sequence analysis of FOXC1 and PITX2 was performed in patients who did not carry a PAX6 mutation. The most common clinical features in the group of aniridia patients associated with aniridia were nystagmus, cataracts and glaucoma...
June 5, 2018: Molecular Medicine Reports
Nike Beaubier, Robert Tell, Robert Huether, Martin Bontrager, Stephen Bush, Jerod Parsons, Kaanan Shah, Tim Baker, Gene Selkov, Tim Taxter, Amber Thomas, Sam Bettis, Aly Khan, Denise Lau, Christina Lee, Matthew Barber, Marcin Cieslik, Casey Frankenberger, Amy Franzen, Ali Weiner, Gary Palmer, Robert Lonigro, Dan Robinson, Yi-Mi Wu, Xuhong Cao, Eric Lefkofsky, Arul Chinnaiyan, Kevin P White
We have developed a clinically validated NGS assay that includes tumor, germline and RNA sequencing. We apply this assay to clinical specimens and cell lines, and we demonstrate a clinical sensitivity of 98.4% and positive predictive value of 100% for the clinically actionable variants measured by the assay. We also demonstrate highly accurate copy number measurements and gene rearrangement identification.
May 25, 2018: Oncotarget
J Sidney Ang, Martin N Aloise, Diana Dawes, Maryn G Dempster, Robert Fraser, Andrea Paterson, Paul Stanley, Adriana Suarez-Gonzalez, Martin Dawes, Hagit Katzov-Eckert
OBJECTIVE: A simple, non-invasive sample collection method is key for the integration of pharmacogenetics into clinical practice. The aim of this study was to gain samples for pharmacogenetic testing and evaluate the variation between dry-flocked and sponge-tipped buccal swabs in yield and quality of DNA isolated. RESULTS: Thirty-one participants collected samples using dry-flocked swabs and sponge-tipped swabs. Samples were assessed for DNA yield, quality and genotyping performance on a qPCR OpenArray platform of 28 pharmacogenetic SNPs and a CYP2D6 TaqMan copy number variant...
June 14, 2018: BMC Research Notes
Ameen Bakhsh, Ioannis Ladas, Marian Hamshere, Martyn Bullock, George Kirov, Lei Zhang, Peter Taylor, John Welbourn Gregory, David Michael Scott-Coombes, Henry Völzke, Alexander Teumer, Kiran Mantripragada, Dillwyn Williams, Roderick J Clifton-Bligh, Nigel Williams, Marian Ludgate
Euthyroid multinodular goiter (MNG) is common but little is known about the genetic variation conferring predisposition. Previously we reported a family with MNG of adolescent onset in which some family members developed papillary thyroid carcinomas (PTC). We conducted a genome-wide linkage analysis and next generation sequencing to identify genetic variants that may confer disease predisposition. A multipoint nonparametric LOD score of 3.01 was obtained covering 19 cM on chromosome 20p. Haplotype analysis reduced the region of interest to 10 cM; analysis of copy number variation identified an intronic InDel (~1000 bp) in the PLCB1 gene in all 8 affected family members and carriers (an unaffected person who has inherited the genetic trait) but ~1% of 'healthy' Caucasians...
June 13, 2018: Thyroid: Official Journal of the American Thyroid Association
Jin Wang, Yan Zhao, Hua Jin, Jing Tao, Luquan Cao, Yan Cai
OBJECTIVE: To assess the value of single nucleotide polymorphism array (SNP array) for the study of fetuses with conotruncal defects (CTD) detected by echocardiography. METHODS: SNP array was carried out on 75 fetuses with sonographically detected CTD but a normal karyotype. The results were analyzed with ChAS software. RESULTS: Pathogenic CNVs were detected in 7 (9.3%) of all cases. Variant of uncertain significance (VOUS) was detected in 2 (2...
June 10, 2018: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
Andrew M Intlekofer, Erel Joffe, Connie L Batlevi, Patrick Hilden, Jie He, Venkatraman E Seshan, Andrew D Zelenetz, M Lia Palomba, Craig H Moskowitz, Carol Portlock, David J Straus, Ariela Noy, Steven M Horwitz, John F Gerecitano, Alison Moskowitz, Paul Hamlin, Matthew J Matasar, Anita Kumar, Marcel R van den Brink, Kristina M Knapp, Janine D Pichardo, Michelle K Nahas, Sally E Trabucco, Tariq Mughal, Amanda R Copeland, Elli Papaemmanuil, Mathai Moarii, Ross L Levine, Ahmet Dogan, Vincent A Miller, Anas Younes
We sought to define the genomic landscape of diffuse large B-cell lymphoma (DLBCL) by using formalin-fixed paraffin-embedded (FFPE) biopsy specimens. We used targeted sequencing of genes altered in hematologic malignancies, including DNA coding sequence for 405 genes, noncoding sequence for 31 genes, and RNA coding sequence for 265 genes (FoundationOne-Heme). Short variants, rearrangements, and copy number alterations were determined. We studied 198 samples (114 de novo, 58 previously treated, and 26 large-cell transformation from follicular lymphoma)...
June 12, 2018: Blood Cancer Journal
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