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Copy number variants

Te-Sha Tsai, Sonika Tyagi, Justin C St John
STUDY QUESTION: What are the molecular differences between mitochondrial DNA (mtDNA)-deficient and mtDNA-normal oocytes and how does mitochondrial supplementation alter these? SUMMARY ANSWER: Changes to DNA methylation in a 5' cytosine-phosphate-guanine 3' (CpG) island in the mtDNA-specific replication factor (DNA polymerase gamma (POLG)) of mtDNA-deficient oocytes mediates an increase in mtDNA copy number by the 2-cell stage that positively modulates the expression of nuclear genes, which affect cellular and metabolic processes, following autologous mitochondrial supplementation...
March 13, 2018: Human Reproduction
Qing Mao, Robert Chin, Weiwei Xie, Yuqing Deng, Wenwei Zhang, Huixin Xu, Rebecca Yu Zhang, Quan Shi, Erin E Peters, Natali Gulbahce, Zhenyu Li, Fang Chen, Radoje Drmanac, Brock A Peters
BACKGROUND: Amniocentesis is a common procedure, the primary purpose of which is to collect cells from the fetus to allow testing for abnormal chromosomes, altered chromosomal copy number, or a small number of genes that have small single- to multibase defects. Here we demonstrate the feasibility of generating an accurate whole-genome sequence of a fetus from either the cellular or cell-free DNA (cfDNA) of an amniotic sample. METHODS: cfDNA and DNA isolated from the cell pellet of 31 amniocenteses were sequenced to approximately 50× genome coverage by use of the Complete Genomics nanoarray platform...
March 15, 2018: Clinical Chemistry
Kelly Kyker-Snowman, Bracha Erlanger Avigdor, Mansoor Nasim, Ashley Cimino-Mathews, Sarah J Wheelan, Pedram Argani, Ben Ho Park
BACKGROUND/PURPOSE: Tumor heterogeneity is a now well-recognized phenomenon that can affect the classification, prognosis and treatment of human cancers. Heterogeneity is often described in primary breast cancers based upon histologic subtypes, hormone- and HER2-receptor status, and immunolabeling for various markers, which can be seen within a single tumor as mixed cellular populations, or as separate discrete foci. EXPERIMENTAL DESIGN/METHODS: Here, we present a case report of a patient's primary breast cancer that had two separate but adjacent histologic components, one that was estrogen receptor (ER) positive, and the other ER negative...
March 15, 2018: Breast Cancer Research and Treatment
Ibtessam R Hussein, Rima S Bader, Adeel G Chaudhary, Randa Bassiouni, Maha Alquaiti, Fai Ashgan, Hans-Juergen Schulten, Mohammad H Al Qahtani
Congenital heart defects (CHDs) are the most common birth defects in neonatal life. CHDs could be presented as isolated defects or associated with developmental delay (DD) and/or other congenital malformations. A small proportion of cardiac defects are caused by chromosomal abnormalities or single gene defects; however, in a large proportion of cases no genetic diagnosis could be achieved by clinical examination and conventional genetic analysis. The development of genome wide array-Comparative Genomic Hybridization technique (array-CGH) allowed for the detection of cryptic chromosomal imbalances and pathogenic copy number variants (CNVs) not detected by conventional techniques...
March 14, 2018: Pediatric Cardiology
Thomas Liehr, Isolde Schreyer, Alma Kuechler, Emmanouil Manolakos, Sylke Singer, Andreas Dufke, Kathleen Wilhelm, Tereza Jančušková, Radek Čmejla, Moneeb A K Othman, Ahmed H Al-Rikabi, Kristin Mrasek, Monika Ziegler, Stefanie Kankel, Katharina Kreskowski, Anja Weise
Background: Copy number variants (CNVs) are the genetic bases for microdeletion/ microduplication syndromes (MMSs). Couples with an affected child and desire to have further children are routinely tested for a potential parental origin of a specific CNV either by molecular karyotyping or by two color fluorescence in situ hybridization (FISH), yet. In the latter case a critical region probe (CRP) is combined with a control probe for identification of the chromosome in question. However, CNVs can arise also due to other reasons, like a recombination-event based on a submicroscopic, cryptic inversion in one of the parents...
2018: Molecular Cytogenetics
Lu Zeng, R Daniel Kortschak, Joy M Raison, Terry Bertozzi, David L Adelson
Transposable Elements (TEs) are mobile DNA sequences that make up significant fractions of amniote genomes. However, they are difficult to detect and annotate ab initio because of their variable features, lengths and clade-specific variants. We have addressed this problem by refining and developing a Comprehensive ab initio Repeat Pipeline (CARP) to identify and cluster TEs and other repetitive sequences in genome assemblies. The pipeline begins with a pairwise alignment using krishna, a custom aligner. Single linkage clustering is then carried out to produce families of repetitive elements...
2018: PloS One
Hema Singh, Pradeep Tiwari, Vijay Bhavi, Praveen Singh Chaudhary, Prashanth Suravajhala, M Krishna Mohan, Sandeep Kumar Mathur
Background: Human height is a classic polygenic trait and currently available data explains only 10% of the phenotypic variation in height. Almost 60%-80% of the children coming to pediatric and endocrinology outpatient department for the evaluation of short stature are still labeled as idiopathic. Objectives: The aim of this study is to identify various chromosomal alterations causing idiopathic short stature (ISS) and short stature with dysmorphic features not pertaining to known genetic syndromes...
January 2018: Indian Journal of Endocrinology and Metabolism
Ryuji Yamamoto, Tsuyoshi Osawa, Yusuke Sasaki, Shogo Yamamoto, Motonobu Anai, Kouji Izumi, Yoshihiro Matsumura, Juro Sakai, Hiroyuki Aburatani, Atsushi Mizokami, Tatsuhiko Kodama, Toshiya Tanaka
The non-POU domain-containing octamer binding protein p54nrb /NONO is a multifunctional nuclear protein involved in RNA splicing, processing, and transcriptional regulation of nuclear hormone receptors. Through chromosome copy number analysis via whole-exome sequencing, we revealed amplification of the chromosome Xq11.22-q21.33 locus containing the androgen receptor ( AR ) and NONO genes in androgen-independent, castration-resistant prostate cancer (CRPC)-like LNCaP-SF cells. Moreover, NONO was frequently amplified and overexpressed in patients with CRPC...
February 13, 2018: Oncotarget
Claudio Toma, Alex D Shaw, Richard J N Allcock, Anna Heath, Kerrie D Pierce, Philip B Mitchell, Peter R Schofield, Janice M Fullerton
Bipolar disorder (BD) is a complex psychiatric condition with high heritability, the genetic architecture of which likely comprises both common variants of small effect and rare variants of higher penetrance, the latter of which are largely unknown. Extended families with high density of illness provide an opportunity to map novel risk genes or consolidate evidence for existing candidates, by identifying genes carrying pathogenic rare variants. We performed whole-exome sequencing (WES) in 15 BD families (117 subjects, of whom 72 were affected), augmented with copy number variant (CNV) microarray data, to examine contributions of multiple classes of rare genetic variants within a familial context...
March 13, 2018: Translational Psychiatry
Kathryn B Manheimer, Nihir Patel, Felix Richter, Joshua Gorham, Angela C Tai, Jason Homsy, Marko T Boskovski, Michael Parfenov, Elizabeth Goldmuntz, Wendy K Chung, Martina Brueckner, Martin Tristani-Firouzi, Deepak Srivastava, Jonathan G Seidman, Christine E Seidman, Bruce D Gelb, Andrew J Sharp
Multiple tools have been developed to identify copy number variants (CNVs) from whole exome (WES) and whole genome sequencing (WGS) data. Current tools such as XHMM for WES and CNVnator for WGS identify CNVs based on changes in read depth. For WGS, other methods to identify CNVs include utilizing discordant read pairs and split reads and genome-wide local assembly with tools such as Lumpy and SvABA, respectively. Here, we introduce a new method to identify deletion CNVs from WES and WGS trio data based on the clustering of Mendelian errors (MEs)...
March 11, 2018: Human Mutation
Jianghong Zhong, Lina M Olsson, Vilma Urbonaviciute, Min Yang, Liselotte Bäckdahl, Rikard Holmdahl
A single nucleotide polymorphism in Ncf1 has been found with a major effect on chronic inflammatory autoimmune diseases in the rat with the surprising observation that a lower reactive oxygen response led to more severe diseases. This finding was subsequently reproduced in the mouse and the effect operates in many different murine diseases through different pathogenic pathways; like models for rheumatoid arthritis, encephalomyelitis, lupus, gout, psoriasis and psoriatic arthritis. The human gene is located in an unstable region with many variable sequence repetitions, which means it has not been included in any genome wide associated screens so far...
March 8, 2018: Free Radical Biology & Medicine
I Maini, I Ivanovski, O Djuric, S G Caraffi, E Errichiello, M Marinelli, F Franchi, V Bizzarri, S Rosato, M Pollazzon, C Gelmini, M Malacarne, C Fusco, G Gargano, S Bernasconi, O Zuffardi, L Garavelli
BACKGROUND: Since 2010, array-CGH (aCGH) has been the first-tier test in the diagnostic approach of children with neurodevelopmental disorders (NDD) or multiple congenital anomalies (MCA) of unknown origin. Its broad application led to the detection of numerous variants of uncertain clinical significance (VOUS). How to appropriately interpret aCGH results represents a challenge for the clinician. METHOD: We present a retrospective study on 293 patients with age range 1 month - 29 years (median 7 years) with NDD and/or MCA and/or dysmorphisms, investigated through aCGH between 2005 and 2016...
March 9, 2018: Italian Journal of Pediatrics
Amihood Singer, Idit Maya, Arie Koifman, Nadra Nasser Samra, Hagit N Baris, Tzipora Falik-Zaccai, Shay Ben Shachar, Lena Sagi-Dain
INTRODUCTION: Fetal echogenic bowel is a frequent sonographic finding, demonstrated in about 1% of pregnancies. The advised evaluation of fetal echogenic bowel includes maternal serology, genetic testing for cystic fibrosis, detailed sonographic anatomic survey, and invasive prenatal testing for fetal chromosomal aberrations. The objective of our study was to evaluate the risk for clinically significant chromosomal microarray analysis (CMA) findings in pregnancies with isolated echogenic bowel...
March 6, 2018: Early Human Development
David R Martin, Elisa LaBauve, Joseph M Pomo, Vi K Chiu, Joshua A Hanson, Rama R Gullapalli
The major categories of pancreatic neuroendocrine tumor (PanNET) are well-differentiated NET and poorly differentiated neuroendocrine carcinoma. Sequencing of these tumors has identified multiple important genes in the pathogenesis of PanNETs, such as DAXX/ATRX, MEN1, TP53, RB, and mTOR pathway genes. We identified a case of well-differentiated PanNET with high-grade progression with simultaneous low- and high-grade histologic regions containing variable genomic profiles. We performed tumor microdissection and analyzed both regions using a 409-gene comprehensive cancer panel using next-generation sequencing in addition to immunohistochemical and morphologic studies...
April 2018: Pancreas
Yukiko Kuroda, Ikuko Ohashi, Takuya Naruto, Kazumi Ida, Yumi Enomoto, Toshiyuki Saito, Jun-Ichi Nagai, Kenji Kurosawa
Ehlers-Danlos syndrome classical type (cEDS) is a connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and joint hypermobility. The condition typically results from mutations in COL5A1 or COL5A2 leading to the functional haploinsufficiency. Here, we report of a 24-year-old male with mild intellectual disability, dysmorphic features, and a phenotype consistent with cEDS. A copy number variant-calling algorithm from panel sequencing data identified the deletions exons 2-11 and duplications of exons 12-67 within COL5A1...
March 9, 2018: Congenital Anomalies
Jacob L Steenwyk, Antonis Rokas
In recent years, copy number (CN) variation has emerged as a new and significant source of genetic polymorphisms contributing to the phenotypic diversity of populations. CN variants are defined as genetic loci that, due to duplication and deletion, vary in their number of copies across individuals in a population. CN variants range in size from 50 base pairs to whole chromosomes, can influence gene activity, and are associated with a wide range of phenotypes in diverse organisms, including the budding yeast Saccharomyces cerevisiae ...
2018: Frontiers in Microbiology
Bradley Peter, Christie L Waddington, Monika Oláhová, Ewen W Sommerville, Sila Hopton, Angela Pyle, Michael Champion, Monika Ohlson, Triinu Siibak, Zofia M A Chrzanowska-Lightowlers, Robert W Taylor, Maria Falkenberg, Robert N Lightowlers
LonP1 is a mitochondrial matrix protease whose selective substrate specificity is essential for maintaining mitochondrial homeostasis. Recessively-inherited, pathogenic defects in LonP1 have been previously reported to underlie cerebral, ocular, dental, auricular and skeletal anomalies (CODAS) syndrome, a complex multisystemic and developmental disorder. Intriguingly, although classical mitochondrial disease presentations are well-known to exhibit marked clinical heterogeneity, the skeletal and dental features associated with CODAS syndrome are pathognomonic...
March 6, 2018: Human Molecular Genetics
Fumio Kasai, Jorge C Pereira, Arihiro Kohara, Malcolm A Ferguson-Smith
Chromosome translocations can be detected by cytogenetic analysis, but it is hard to characterize the breakpoints at the sequence level. Chromosome sorting by flow cytometry produces flow karyotypes that enable the isolation of abnormal chromosomes and the generation of chromosome-specific DNA. In this study, a derivative chromosome t(9; 14) and its homologous normal chromosomes 9 and 14 from the Ishikawa 3-H-12 cell line were sorted to collect homologue-specific samples. Chromosome sequencing identified the breakpoint junction in the der(9) at 9p24...
March 6, 2018: DNA Research: An International Journal for Rapid Publication of Reports on Genes and Genomes
Jose Luis Royo, Joan Valls, Rafael D Acemel, Carlos Gómez-Marin, Mariona Pascual-Pons, Arantxa Lupiañez, Jose Luis Gomez-Skarmeta, Joan Fibla
Previous reports have proposed that personality may have played a role on human Out-Of-Africa migration, pinpointing some genetic variants that were positively selected in the migrating populations. In this work, we discuss the role of a common copy-number variant within the SIRPB1 gene, recently associated with impulsive behavior, in the human Out-Of-Africa migration. With the analysis of the variant distribution across forty-two different populations, we found that the SIRPB1 haplotype containing duplicated allele significantly correlated with human migratory distance, being one of the few examples of positively selected loci found across the human world colonization...
2018: PloS One
Johanna C Herkert, Kristin M Abbott, Erwin Birnie, Martine T Meems-Veldhuis, Ludolf G Boven, Marloes Benjamins, Gideon J du Marchie Sarvaas, Daniela Q C M Barge-Schaapveld, J Peter van Tintelen, Paul A van der Zwaag, Yvonne J Vos, Richard J Sinke, Maarten P van den Berg, Irene M van Langen, Jan D H Jongbloed
PurposeWe evaluated the diagnostic yield in pediatric dilated cardiomyopathy (DCM) of combining exome sequencing (ES)-based targeted analysis and genome-wide copy-number variation (CNV) analysis. Based on our findings, we retrospectively designed an effective approach for genetic testing in pediatric DCM.MethodsWe identified 95 patients (in 85 families) with pediatric onset of DCM. We initially excluded 13 of these families because they already had a genetic diagnosis, leaving a total of 31 probands for single-nucleotide polymorphism (SNP) array and trio-ES...
March 8, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
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