Beta Globin (HBB) Sequencing and Deletion/Duplication (Temporary Referral As of 12/07/20) ARUP Test Code 2010117 Beta Globin (HBB) Seq, Del/Dup Spcm Whole Blood
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Diagnosis of Sickle Cell Disease and HBB Haplotyping in the Era of Personalized Medicine: Role of Next Generation Sequencing
Journal of Personalized Medicine Article Diagnosis of Sickle Cell Disease and HBB Haplotyping in the Era of Personalized Medicine: Role of Next Generation Sequencing Adekunle Adekile 1,*, Nagihan Akbulut-Jeradi 2, Rasha Al Khaldi 2, Maria Jinky Fernandez 2 and Jalaja Sukumaran 1 1 Department of Pediatrics, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait; jalajasukumaran@hotmail 2 Advanced Technology Company, Hawali 32060, Kuwait; [email protected] (N.A.-J.); [email protected] (R.A.); [email protected] (M.J.F.) * Correspondence: [email protected]; Tel.: +965-253-194-86 Abstract: Hemoglobin genotype and HBB haplotype are established genetic factors that modify the clinical phenotype in sickle cell disease (SCD). Current methods of establishing these two factors are cumbersome and/or prone to errors. The throughput capability of next generation sequencing (NGS) makes it ideal for simultaneous interrogation of the many genes of interest in SCD. This study was designed to confirm the diagnosis in patients with HbSS and Sβ-thalassemia, identify any ß-thal mutations and simultaneously determine the ßS HBB haplotype. Illumina Ampliseq custom DNA panel was used to genotype the DNA samples. Haplotyping was based on the alleles on five haplotype-specific SNPs. The patients studied included 159 HbSS patients and 68 Sβ-thal patients, previously diagnosed using high performance liquid chromatography (HPLC). There was Citation: Adekile, A.; considerable discordance between HPLC and NGS results, giving a false +ve rate of 20.5% with a S Akbulut-Jeradi, N.; Al Khaldi, R.; sensitivity of 79% for the identification of Sβthal. -
Identifying and Mapping Cell-Type-Specific Chromatin PNAS PLUS Programming of Gene Expression
Identifying and mapping cell-type-specific chromatin PNAS PLUS programming of gene expression Troels T. Marstranda and John D. Storeya,b,1 aLewis-Sigler Institute for Integrative Genomics, and bDepartment of Molecular Biology, Princeton University, Princeton, NJ 08544 Edited by Wing Hung Wong, Stanford University, Stanford, CA, and approved January 2, 2014 (received for review July 2, 2013) A problem of substantial interest is to systematically map variation Relating DHS to gene-expression levels across multiple cell in chromatin structure to gene-expression regulation across con- types is challenging because the DHS represents a continuous ditions, environments, or differentiated cell types. We developed variable along the genome not bound to any specific region, and and applied a quantitative framework for determining the exis- the relationship between DHS and gene expression is largely tence, strength, and type of relationship between high-resolution uncharacterized. To exploit variation across cell types and test chromatin structure in terms of DNaseI hypersensitivity and genome- for cell-type-specific relationships between DHS and gene expres- wide gene-expression levels in 20 diverse human cell types. We sion, the measurement units must be placed on a common scale, show that ∼25% of genes show cell-type-specific expression ex- the continuous DHS measure associated to each gene in a well- plained by alterations in chromatin structure. We find that distal defined manner, and all measurements considered simultaneously. regions of chromatin structure (e.g., ±200 kb) capture more genes Moreover, the chromatin and gene-expression relationship may with this relationship than local regions (e.g., ±2.5 kb), yet the local only manifest in a single cell type, making standard measures of regions show a more pronounced effect. -
Hypoxia-Induced Alpha-Globin Expression in Syncytiotrophoblasts Mimics the Pattern Observed in Preeclamptic Placentas
International Journal of Molecular Sciences Article Hypoxia-Induced Alpha-Globin Expression in Syncytiotrophoblasts Mimics the Pattern Observed in Preeclamptic Placentas Zahra Masoumi 1,* , Lena Erlandsson 1, Eva Hansson 1, Mattias Magnusson 2, Eva Mezey 3 and Stefan R. Hansson 1,4 1 Department of Clinical Sciences Lund, Division of Obstetrics and Gynecology, Lund University, SE-22184 Lund, Sweden; [email protected] (L.E.); [email protected] (E.H.); [email protected] (S.R.H.) 2 Department of Molecular Medicine and Gene Therapy, Lund University, SE-22184 Lund, Sweden; [email protected] 3 Adult Stem Cell Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA; [email protected] 4 Skåne University Hospital, SE-22184 Lund, Sweden * Correspondence: [email protected] Abstract: Preeclampsia (PE) is a pregnancy disorder associated with placental dysfunction and elevated fetal hemoglobin (HbF). Early in pregnancy the placenta harbors hematopoietic stem and progenitor cells (HSPCs) and is an extramedullary source of erythropoiesis. However, globin ex- pression is not unique to erythroid cells and can be triggered by hypoxia. To investigate the role of the placenta in increasing globin levels previously reported in PE, flow cytometry, histological and Citation: Masoumi, Z.; Erlandsson, immunostaining and in situ analyses were used on placenta samples and ex vivo explant cultures. L.; Hansson, E.; Magnusson, M.; Our results indicated that in PE pregnancies, placental HSPC homing and erythropoiesis were not Mezey, E.; Hansson, S.R. affected. Non-erythroid alpha-globin mRNA and protein, but not gamma-globin, were detected in Hypoxia-Induced Alpha-Globin Expression in Syncytiotrophoblasts syncytiotrophoblasts and stroma of PE placenta samples. -
No Evidence for Transvection in Vivo by a Superenhancer:Promoter Pair
bioRxiv preprint doi: https://doi.org/10.1101/393363; this version posted August 16, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 No evidence for transvection in vivo by a superenhancer:promoter 2 pair integrated into identical open chromatin at the Rosa26 locus 3 4 Keiji Tanimoto1, 2, *, Hitomi Matsuzaki1, 2, Eiichi Okamura3, Aki Ushiki2, Akiyoshi 5 Fukamizu1, 2, and James Douglas Engel4 6 7 1 Faculty of Life and Environmental Sciences, Life Science Center for Survival Dynamics, 8 Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki 9 305-8577, Japan 10 2 Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 11 305-8577, Japan 12 3 Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan 13 4 Department of Cell and Developmental Biology, University of Michigan, USA 14 15 16 17 * Corresponding author: Faculty of Life and Environmental Sciences, 18 University of Tsukuba, Tennoudai 1-1-1 19 Tsukuba, Ibaraki 305-8577, Japan 20 Phone/Fax: (+81) 29-853-6070 21 E-mail: [email protected] 22 1 bioRxiv preprint doi: https://doi.org/10.1101/393363; this version posted August 16, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. -
CTCF-Dependent Enhancer-Blocking by Alternative Chromatin Loop Formation
CTCF-dependent enhancer-blocking by alternative chromatin loop formation Chunhui Houa, Hui Zhaoa,1, Keiji Tanimotob, and Ann Deana,2 aLaboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892; and bGraduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, 305-8577, Japan Edited by Gary Felsenfeld, National Institutes of Health, Bethesda, MD, and approved November 1, 2008 (received for review August 27, 2008) The mechanism underlying enhancer-blocking by insulators is expressed (14, 15). However, the function of HS5 in vivo is not unclear. We explored the activity of human -globin HS5, the clear. Chromosomal deletion of mouse HS5 had no significant orthologue of the CTCF-dependent chicken HS4 insulator. An extra effect on -globin expression or on silent odorant receptor genes copy of HS5 placed between the -globin locus control region (LCR) located downstream of HS5, indicating that HS5 is not required and downstream genes on a transgene fulfills the classic predic- as an insulator at its endogenous location (16, 17). In contrast, tions for an enhancer-blocker. Ectopic HS5 does not perturb the LCR an ectopic globin gene placed upstream in a human transgenic but blocks gene activation by interfering with RNA pol II, activator globin locus, and separated from the LCR by HS5, failed to be and coactivator recruitment, and epigenetic modification at the activated, although some evidence suggested the blocking varied downstream -globin gene. Underlying these effects, ectopic HS5 in a developmental stage-specific fashion (18, 19). disrupts chromatin loop formation between -globin and the LCR, Earlier studies suggested that human HS5 could function as a and instead forms a new loop with endogenous HS5 that topo- transcriptional enhancer-blocker when placed between the LCR logically isolates the LCR. -
Serum Albumin OS=Homo Sapiens
Protein Name Cluster of Glial fibrillary acidic protein OS=Homo sapiens GN=GFAP PE=1 SV=1 (P14136) Serum albumin OS=Homo sapiens GN=ALB PE=1 SV=2 Cluster of Isoform 3 of Plectin OS=Homo sapiens GN=PLEC (Q15149-3) Cluster of Hemoglobin subunit beta OS=Homo sapiens GN=HBB PE=1 SV=2 (P68871) Vimentin OS=Homo sapiens GN=VIM PE=1 SV=4 Cluster of Tubulin beta-3 chain OS=Homo sapiens GN=TUBB3 PE=1 SV=2 (Q13509) Cluster of Actin, cytoplasmic 1 OS=Homo sapiens GN=ACTB PE=1 SV=1 (P60709) Cluster of Tubulin alpha-1B chain OS=Homo sapiens GN=TUBA1B PE=1 SV=1 (P68363) Cluster of Isoform 2 of Spectrin alpha chain, non-erythrocytic 1 OS=Homo sapiens GN=SPTAN1 (Q13813-2) Hemoglobin subunit alpha OS=Homo sapiens GN=HBA1 PE=1 SV=2 Cluster of Spectrin beta chain, non-erythrocytic 1 OS=Homo sapiens GN=SPTBN1 PE=1 SV=2 (Q01082) Cluster of Pyruvate kinase isozymes M1/M2 OS=Homo sapiens GN=PKM PE=1 SV=4 (P14618) Glyceraldehyde-3-phosphate dehydrogenase OS=Homo sapiens GN=GAPDH PE=1 SV=3 Clathrin heavy chain 1 OS=Homo sapiens GN=CLTC PE=1 SV=5 Filamin-A OS=Homo sapiens GN=FLNA PE=1 SV=4 Cytoplasmic dynein 1 heavy chain 1 OS=Homo sapiens GN=DYNC1H1 PE=1 SV=5 Cluster of ATPase, Na+/K+ transporting, alpha 2 (+) polypeptide OS=Homo sapiens GN=ATP1A2 PE=3 SV=1 (B1AKY9) Fibrinogen beta chain OS=Homo sapiens GN=FGB PE=1 SV=2 Fibrinogen alpha chain OS=Homo sapiens GN=FGA PE=1 SV=2 Dihydropyrimidinase-related protein 2 OS=Homo sapiens GN=DPYSL2 PE=1 SV=1 Cluster of Alpha-actinin-1 OS=Homo sapiens GN=ACTN1 PE=1 SV=2 (P12814) 60 kDa heat shock protein, mitochondrial OS=Homo -
Adult, Embryonic and Fetal Hemoglobin Are Expressed in Human Glioblastoma Cells
514 INTERNATIONAL JOURNAL OF ONCOLOGY 44: 514-520, 2014 Adult, embryonic and fetal hemoglobin are expressed in human glioblastoma cells MARWAN EMARA1,2, A. ROBERT TURNER1 and JOAN ALLALUNIS-TURNER1 1Department of Oncology, University of Alberta and Alberta Health Services, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada; 2Center for Aging and Associated Diseases, Zewail City of Science and Technology, Cairo, Egypt Received September 7, 2013; Accepted October 7, 2013 DOI: 10.3892/ijo.2013.2186 Abstract. Hemoglobin is a hemoprotein, produced mainly in Introduction erythrocytes circulating in the blood. However, non-erythroid hemoglobins have been previously reported in other cell Globins are hemo-containing proteins, have the ability to types including human and rodent neurons of embryonic bind gaseous ligands [oxygen (O2), nitric oxide (NO) and and adult brain, but not astrocytes and oligodendrocytes. carbon monoxide (CO)] reversibly. They have been described Human glioblastoma multiforme (GBM) is the most aggres- in prokaryotes, fungi, plants and animals with an enormous sive tumor among gliomas. However, despite extensive basic diversity of structure and function (1). To date, hemoglobin, and clinical research studies on GBM cells, little is known myoglobin, neuroglobin (Ngb) and cytoglobin (Cygb) repre- about glial defence mechanisms that allow these cells to sent the vertebrate globin family with distinct function and survive and resist various types of treatment. We have tissue distributions (2). During ontogeny, developing erythro- shown previously that the newest members of vertebrate blasts sequentially express embryonic {[Gower 1 (ζ2ε2), globin family, neuroglobin (Ngb) and cytoglobin (Cygb), are Gower 2 (α2ε2), and Portland 1 (ζ2γ2)] to fetal [Hb F(α2γ2)] expressed in human GBM cells. -
Technical Note, Appendix: an Analysis of Blood Processing Methods to Prepare Samples for Genechip® Expression Profiling (Pdf, 1
Appendix 1: Signature genes for different blood cell types. Blood Cell Type Source Probe Set Description Symbol Blood Cell Type Source Probe Set Description Symbol Fraction ID Fraction ID Mono- Lympho- GSK 203547_at CD4 antigen (p55) CD4 Whitney et al. 209813_x_at T cell receptor TRG nuclear cytes gamma locus cells Whitney et al. 209995_s_at T-cell leukemia/ TCL1A Whitney et al. 203104_at colony stimulating CSF1R lymphoma 1A factor 1 receptor, Whitney et al. 210164_at granzyme B GZMB formerly McDonough (granzyme 2, feline sarcoma viral cytotoxic T-lymphocyte- (v-fms) oncogene associated serine homolog esterase 1) Whitney et al. 203290_at major histocompatibility HLA-DQA1 Whitney et al. 210321_at similar to granzyme B CTLA1 complex, class II, (granzyme 2, cytotoxic DQ alpha 1 T-lymphocyte-associated Whitney et al. 203413_at NEL-like 2 (chicken) NELL2 serine esterase 1) Whitney et al. 203828_s_at natural killer cell NK4 (H. sapiens) transcript 4 Whitney et al. 212827_at immunoglobulin heavy IGHM Whitney et al. 203932_at major histocompatibility HLA-DMB constant mu complex, class II, Whitney et al. 212998_x_at major histocompatibility HLA-DQB1 DM beta complex, class II, Whitney et al. 204655_at chemokine (C-C motif) CCL5 DQ beta 1 ligand 5 Whitney et al. 212999_x_at major histocompatibility HLA-DQB Whitney et al. 204661_at CDW52 antigen CDW52 complex, class II, (CAMPATH-1 antigen) DQ beta 1 Whitney et al. 205049_s_at CD79A antigen CD79A Whitney et al. 213193_x_at T cell receptor beta locus TRB (immunoglobulin- Whitney et al. 213425_at Homo sapiens cDNA associated alpha) FLJ11441 fis, clone Whitney et al. 205291_at interleukin 2 receptor, IL2RB HEMBA1001323, beta mRNA sequence Whitney et al. -
Molecular Basis of the Function of Transcriptional Enhancers
cells Review Molecular Basis of the Function of Transcriptional Enhancers 1,2, 1, 1,3, Airat N. Ibragimov y, Oleg V. Bylino y and Yulii V. Shidlovskii * 1 Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334 Moscow, Russia; [email protected] (A.N.I.); [email protected] (O.V.B.) 2 Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334 Moscow, Russia 3 I.M. Sechenov First Moscow State Medical University, 8, bldg. 2 Trubetskaya St., 119048 Moscow, Russia * Correspondence: [email protected]; Tel.: +7-4991354096 These authors contributed equally to this study. y Received: 30 May 2020; Accepted: 3 July 2020; Published: 5 July 2020 Abstract: Transcriptional enhancers are major genomic elements that control gene activity in eukaryotes. Recent studies provided deeper insight into the temporal and spatial organization of transcription in the nucleus, the role of non-coding RNAs in the process, and the epigenetic control of gene expression. Thus, multiple molecular details of enhancer functioning were revealed. Here, we describe the recent data and models of molecular organization of enhancer-driven transcription. Keywords: enhancer; promoter; chromatin; transcriptional bursting; transcription factories; enhancer RNA; epigenetic marks 1. Introduction Gene transcription is precisely organized in time and space. The process requires the participation of hundreds of molecules, which form an extensive interaction network. Substantial progress was achieved recently in our understanding of the molecular processes that take place in the cell nucleus (e.g., see [1–9]). -
Molecular Epidemiology and Hematologic Characterization of Δβ
Jiang et al. BMC Medical Genetics (2020) 21:43 https://doi.org/10.1186/s12881-020-0981-x RESEARCH ARTICLE Open Access Molecular epidemiology and hematologic characterization of δβ-thalassemia and hereditary persistence of fetal hemoglobin in 125,661 families of greater Guangzhou area, the metropolis of southern China Fan Jiang1,2, Liandong Zuo2, Dongzhi Li2, Jian Li2, Xuewei Tang2, Guilan Chen2, Jianying Zhou2, Hang Lu2 and Can Liao1,2* Abstract Background: Individuals with δβ-thalassemia/HPFH and β-thalassemia usually present with intermedia or thalassemia major. No large-scale survey on HPFH/δβ-thalassemia in southern China has been reported to date. The purpose of this study was to examine the molecular epidemiology and hematologic characteristics of these disorders in Guangzhou, the largest city in Southern China, to offer advice for thalassemia screening programs and genetic counseling. Methods: A total of 125,661 couples participated in pregestational thalassemia screening. 654 subjects with fetal hemoglobin (HbF) level ≥ 5% were selected for further investigation. Gap-PCR combined with Multiplex ligation dependent probe amplification (MLPA) was used to screen for β-globin gene cluster deletions. Gene sequencing for the promoter region of HBG1 /HBG2 gene was performed for all those subjects. Results: A total of 654 individuals had hemoglobin (HbF) levels≥5, and 0.12% of the couples were found to be heterozygous for HPFH/δβ-thalassemia, including Chinese Gγ (Aγδβ)0-thal, Southeast Asia HPFH (SEA-HPFH), Taiwanese deletion and Hb Lepore–Boston–Washington. The highest prevalence was observed in the Huadu district and the lowest in the Nansha district. Three cases were identified as carrying β-globin gene cluster deletions, which had not been previously reported. -
Identification of Novel HPFH-Like Mutations by CRISPR Base Editing That Elevates the Expression of Fetal Hemoglobin
bioRxiv preprint doi: https://doi.org/10.1101/2020.06.30.178715; this version posted July 1, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Identification of novel HPFH-like mutations by CRISPR base editing that elevates the expression of fetal hemoglobin Nithin Sam Ravi1,3, Beeke Wienert4,8,9, Stacia K. Wyman4, Jonathan Vu4, Aswin Anand Pai2, Poonkuzhali Balasubramanian2, Yukio Nakamura7, Ryo Kurita10, Srujan Marepally1, Saravanabhavan Thangavel1, Shaji R. Velayudhan1,2, Alok Srivastava1,2, Mark A. DeWitt 4,5, Jacob E. Corn4,6, Kumarasamypet M. Mohankumar1* 1. Centre for Stem Cell Research (a unit of inStem, Bengaluru), Christian Medical College Campus, Bagayam, Vellore-632002, Tamil Nadu, India. 2. Department of Haematology, Christian Medical College Hospital, IDA Scudder Rd, Vellore-632002, Tamil Nadu, India. 3. Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram - 695 011, Kerala, India. 4. Innovative Genomics Institute, University of California Berkeley, Berkeley, California- 94704, USA. 5. Department of Microbiology, Immunology, and Molecular Genetics, University of California - Los Angeles, Los Angeles, California - 90095, USA. 6. Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Otto-Stern- Weg, Zurich - 8092, Switzerland. 7. Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan. 8. Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, California -94158, USA 9. School of Biotechnology and Biomolecular Sciences, University of New South Wales - 2052, Sydney, Australia. 10. Research and Development Department Central Blood Institute Blood Service Headquarters Japanese Red Cross Society, 2-1-67 Tatsumi, Tokyo, 135-8521, Japan *Corresponding Author: Dr. -
Hemoglobin Sickle D Punjab—A Case Report
154 Case Report Hemoglobin sickle D Punjab—a case report M. B. Mukherjee, R. R. Surve, R. R. Gangakhedkar, D. Mohanty, R. B. Colah Institute of Immunohaematology, Parel, Mumbai, India. Case History Compound heterozygosity for βS/βD results in a severe hemolytic anemia and a clinical syndrome similar to that of sickle cell disease. Here, we report a case of HbSD Punjab disease. A 10 year old female child residing at Nagpur, A 10 year old female child from Nagpur was referred Maharashtra presented with severe hemolytic anemia, to us with severe hemolytic anemia, occasional episodes hepatosplenomegaly and occasional pains in bones and of pains (predominantly bones and abdomen) associ- abdomen. Initially, she was thought to be a case of sickle cell anemia, however, with the help of HPLC and molecu- ated with fever. She had also received three units of lar analysis it was confirmed as HbSD Punjab disease. blood. Physical examination revealed short stature Key words: HbSD Punjab, Sickle cell disease, Haplotype, (weight 12.5 kg and height 105 cm), pallor, hepatome- α-geonotype galy (2 cm) and splenomegaly (3 cm) below the right and left costal margins respectively. Cardiovascular, res- piratory and nervous systems were normal. HbD Punjab also known as HbD Los Angeles is a β- chain variant and is characterized by a Glu→Gln sub- Investigations stitution at codon 121 with a GAA→CAA change at the DNA level and the electrophotetic mobility at alkaline Her Hb was 5.9 g/dl and the reticulocyte count was pH is similar to HbS (β6, Glu→Val).[1] HbD has been 3.3%.