Erciyes Medical Genetics Days 2019
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Identifying Novel Disease-Associated Variants and Understanding The
Identifying Novel Disease-variants and Understanding the Role of the STAT1-STAT4 Locus in SLE A dissertation submitted to the Graduate School of University of Cincinnati In partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Immunology Graduate Program of the College of Medicine by Zubin H. Patel B.S., Worcester Polytechnic Institute, 2009 John B. Harley, M.D., Ph.D. Committee Chair Gurjit Khurana Hershey, M.D., Ph.D Leah C. Kottyan, Ph.D. Harinder Singh, Ph.D. Matthew T. Weirauch, Ph.D. Abstract Systemic Lupus Erythematosus (SLE) or lupus is an autoimmune disorder caused by an overactive immune system with dysregulation of both innate and adaptive immune pathways. It can affect all major organ systems and may lead to inflammation of the serosal and mucosal surfaces. The pathogenesis of lupus is driven by genetic factors, environmental factors, and gene-environment interactions. Heredity accounts for a substantial proportion of SLE risk, and the role of specific genetic risk loci has been well established. Identifying the specific causal genetic variants and the underlying molecular mechanisms has been a major area of investigation. This thesis describes efforts to develop an analytical approach to identify candidate rare variants from trio analyses and a fine-mapping analysis at the STAT1-STAT4 locus, a well-replicated SLE-risk locus. For the STAT1-STAT4 locus, subsequent functional biological studies demonstrated genotype dependent gene expression, transcription factor binding, and DNA regulatory activity. Rare variants are classified as variants across the genome with an allele-frequency less than 1% in ancestral populations. -
The National Economic Burden of Rare Disease Study February 2021
Acknowledgements This study was sponsored by the EveryLife Foundation for Rare Diseases and made possible through the collaborative efforts of the national rare disease community and key stakeholders. The EveryLife Foundation thanks all those who shared their expertise and insights to provide invaluable input to the study including: the Lewin Group, the EveryLife Community Congress membership, the Technical Advisory Group for this study, leadership from the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH), the Undiagnosed Diseases Network (UDN), the Little Hercules Foundation, the Rare Disease Legislative Advocates (RDLA) Advisory Committee, SmithSolve, and our study funders. Most especially, we thank the members of our rare disease patient and caregiver community who participated in this effort and have helped to transform their lived experience into quantifiable data. LEWIN GROUP PROJECT STAFF Grace Yang, MPA, MA, Vice President Inna Cintina, PhD, Senior Consultant Matt Zhou, BS, Research Consultant Daniel Emont, MPH, Research Consultant Janice Lin, BS, Consultant Samuel Kallman, BA, BS, Research Consultant EVERYLIFE FOUNDATION PROJECT STAFF Annie Kennedy, BS, Chief of Policy and Advocacy Julia Jenkins, BA, Executive Director Jamie Sullivan, MPH, Director of Policy TECHNICAL ADVISORY GROUP Annie Kennedy, BS, Chief of Policy & Advocacy, EveryLife Foundation for Rare Diseases Anne Pariser, MD, Director, Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health Elisabeth M. Oehrlein, PhD, MS, Senior Director, Research and Programs, National Health Council Christina Hartman, Senior Director of Advocacy, The Assistance Fund Kathleen Stratton, National Academies of Science, Engineering and Medicine (NASEM) Steve Silvestri, Director, Government Affairs, Neurocrine Biosciences Inc. -
Klinefelter Syndrome) at 9 Years of Age
17th SSBP International Research Symposium Developmental trajectories of behavioural phenotypes Programme Book 10–13 October 2014 • New York, USA 2 17th International SSBP Research Symposium The Society for the Study 3 of Behavioural Phenotypes 10th – 13th October 2014 The 17th SSBP International Meeting Developmental Trajectories of Behavioural Phenotypes New York, USA 10th – 13th October 2014, New York, USA Contents Contents Welcome ........................................................................................................................................................................................................9 New York Conference Organiser ..............................................................................................................................................10 Scientific Committee ..........................................................................................................................................................................11 4 The SSBP .......................................................................................................................................................................................................12 The SSBP Executive Committee : ...........................................................................................................................................................................12 Meetings of the SSBP ....................................................................................................................................................................................................13 -
The Struggle to Find Reliable Results in Exome Sequencing Data
View metadata, citation and similar papers at core.ac.uk brought to you by CORE METHODS ARTICLEprovided by Frontiers - Publisher Connector published: 12 February 2014 doi: 10.3389/fgene.2014.00016 The struggle to find reliable results in exome sequencing data: filtering out Mendelian errors Zubin H. Patel 1,2 †, Leah C. Kottyan1,3 †, Sara Lazaro1,3 , Marc S. Williams 4 , David H. Ledbetter 4 , GerardTromp 4 , Andrew Rupert 5 , Mojtaba Kohram 5 , Michael Wagner 5 , Ammar Husami 6 , Yaping Qian 6 , C. Alexander Valencia 6 , Kejian Zhang 6 , Margaret K. Hostetter 7 , John B. Harley 1,3 and Kenneth M. Kaufman1,3 * 1 Division of Rheumatology, Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA 2 Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA 3 Department of Veterans Affairs, Veterans Affairs Medical Center – Cincinnati, Cincinnati, OH, USA 4 Genomic Medicine Institute, Geisinger Health System, Danville, PA, USA 5 Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA 6 Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA 7 Division of Infectious Disease, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Edited by: Next Generation Sequencing studies generate a large quantity of genetic data in a Helena Kuivaniemi, Geisinger Health relatively cost and time efficient manner and provide an unprecedented opportunity to System, USA identify candidate causative variants that lead to disease phenotypes. A challenge to these Reviewed by: studies is the generation of sequencing artifacts by current technologies. To identify and Tatiana Foroud, Indiana University School of Medicine, USA characterize the properties that distinguish false positive variants from true variants, we Goo Jun, University of Michigan, USA sequenced a child and both parents (one trio) using DNA isolated from three sources *Correspondence: (blood, buccal cells, and saliva). -
Orphanet Report Series Rare Diseases Collection
Marche des Maladies Rares – Alliance Maladies Rares Orphanet Report Series Rare Diseases collection DecemberOctober 2013 2009 List of rare diseases and synonyms Listed in alphabetical order www.orpha.net 20102206 Rare diseases listed in alphabetical order ORPHA ORPHA ORPHA Disease name Disease name Disease name Number Number Number 289157 1-alpha-hydroxylase deficiency 309127 3-hydroxyacyl-CoA dehydrogenase 228384 5q14.3 microdeletion syndrome deficiency 293948 1p21.3 microdeletion syndrome 314655 5q31.3 microdeletion syndrome 939 3-hydroxyisobutyric aciduria 1606 1p36 deletion syndrome 228415 5q35 microduplication syndrome 2616 3M syndrome 250989 1q21.1 microdeletion syndrome 96125 6p subtelomeric deletion syndrome 2616 3-M syndrome 250994 1q21.1 microduplication syndrome 251046 6p22 microdeletion syndrome 293843 3MC syndrome 250999 1q41q42 microdeletion syndrome 96125 6p25 microdeletion syndrome 6 3-methylcrotonylglycinuria 250999 1q41-q42 microdeletion syndrome 99135 6-phosphogluconate dehydrogenase 67046 3-methylglutaconic aciduria type 1 deficiency 238769 1q44 microdeletion syndrome 111 3-methylglutaconic aciduria type 2 13 6-pyruvoyl-tetrahydropterin synthase 976 2,8 dihydroxyadenine urolithiasis deficiency 67047 3-methylglutaconic aciduria type 3 869 2A syndrome 75857 6q terminal deletion 67048 3-methylglutaconic aciduria type 4 79154 2-aminoadipic 2-oxoadipic aciduria 171829 6q16 deletion syndrome 66634 3-methylglutaconic aciduria type 5 19 2-hydroxyglutaric acidemia 251056 6q25 microdeletion syndrome 352328 3-methylglutaconic -
Inside This Issue
Winter 2014 No. 77 Inside this issue Group News | Fundraising | Members’ Letters | One Family Living with Two Different Chromosome Disorders | Bristol Conference 2014 | Unique Leaflets | Christmas Card Order Form Sophie, Unique’s Chair of Trustees Dear Members, In the past month a few things have reminded me of why it is so important to make connections through Unique but also to draw support from other parents around us. I’ve just returned from Unique’s most recent family conference in Bristol where 150 of us parents and carers had a lovely time in workshops, meals and activities, chatting and watching our children milling around together like one big family since – although we had never met before – we have shared so many experiences in common. However in contrast I have also just met a new mum who has just moved to my area from far away with two toddlers, one with a rare joys of the internet, it is becoming easier to meet others with similar, chromosome disorder, who is starting from scratch with no even very rare, chromosome disorders around the world and to find professional, medical or social support. She reminds me of how yourself talking to them in the middle of the night about some lonely I felt when Max was newly diagnosed, when I knew no one interesting things our children share in common (obsession with with a disabled child let alone anyone with a rare chromosome catalogues, anyone?) And of course we also have an enormous disorder. Elsewhere our latest Unique Facebook group, Unique amount in common with so many parents of children with other Russia, is also just starting up – so far it includes just a small special needs or disabilities around us in our own communities who number of members sharing very different experiences to mine here will often be walking the same path as us. -
BIOINFORMATICS Pages 1–9
Vol. 00 no. 00 2012 BIOINFORMATICS Pages 1–9 DELISHUS: An Efficient and Exact Algorithm for Genome-Wide Detection of Deletion Polymorphism in Autism Derek Aguiar 1;2, Bjarni V. Halldorsson´ 3, Eric M. Morrow ∗;4;5, Sorin Istrail ∗;1;2 1Department of Computer Science, Brown University, Providence, RI, USA 2Center for Computational Molecular Biology, Brown University, Providence, RI, USA 3School of Science and Engineering, Reykjavik University, Reykjavik, Iceland 4Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA 5Department of Psychiatry and Human Behavior, Brown University, Providence, RI, USA Received on XXXXX; revised on XXXXX; accepted on XXXXX Associate Editor: XXXXXXX ABSTRACT mutations with severe effects is more commonly being viewed as a Motivation: The understanding of the genetic determinants of com- major component of disease (McClellan and King, 2010). Phenoty- plex disease is undergoing a paradigm shift. Genetic heterogeneity pic heterogeneity – a large collection of individually rare or personal of rare mutations with deleterious effects is more commonly being conditions – is associated with a higher genetic heterogeneity than viewed as a major component of disease. Autism is an excellent previously assumed. This heterogeneity spectrum can be summari- example where research is active in identifying matches between the zed as follows: (i) individually rare mutations collectively explain phenotypic and genomic heterogeneities. A considerable portion of a large portion of complex disease; (ii) a single gene may contain autism appears to be correlated with copy number variation, which many severe but rare mutations in unrelated individuals; (iii) the is not directly probed by single nucleotide polymorphism (SNP) array same mutation may lead to different clinical conditions in different or sequencing technologies. -
Female Polysomy-X and Systemic Lupus Erythematosus
Seminars in Arthritis and Rheumatism 43 (2014) 508–512 Contents lists available at ScienceDirect Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit Female polysomy-X and systemic lupus erythematosus Mordechai Slae, MDa,n, Merav Heshin-Bekenstein, MDb, Ari Simckes, MDb, Gali Heimer, MDb, Dan Engelhard, MDb, Eli M. Eisenstein, MDc a Department of Pediatrics, University of Alberta Hospital, Edmonton, Alberta, Canada b Department of Pediatrics, Hadassah-Hebrew University Hospital at Ein Kerem, Jerusalem, Israel c Department of Pediatrics, Hadassah-Hebrew University Hospital at Mount-Scopus, Jerusalem, Israel article info abstract Objectives: Systemic lupus erythematosus (SLE) occurs more commonly in females than in males. Recent Keywords: evidence suggests that genetic factors transmitted by the X-chromosome may confer increased risk for Gene dosage autoimmune disease in general, and for SLE in particular. It is therefore possible that X-chromosome Lupus genetics polysomy might confer further increased risk for lupus. In addition to describing the clinical and Polysomy-X immunologic features of a young woman with polysomy-X and SLE, we sought to review all other Sex differences published cases associating female or male polysomy-X with SLE or other forms of autoimmunity. SLE Methods: We report a case of a prepubertal girl with polysomy-X and SLE. We performed a systemic X-chromosome literature review for cases of polysomy-X and SLE and summarize previously published cases. In addition, we reviewed reports concerning the possible association between SLE and other connective tissue diseases and male polysomy-X. Results: An 11-year-old girl with tetrasomy-X (48 XXXX karyotype) presented with prolonged fever. -
Genetic Evaluation of Inpatient Neonatal and Infantile Congenital Heart Defects: New Findings and Review of the Literature
G C A T T A C G G C A T genes Article Genetic Evaluation of Inpatient Neonatal and Infantile Congenital Heart Defects: New Findings and Review of the Literature Benjamin M. Helm 1,2,*, Benjamin J. Landis 3 and Stephanie M. Ware 1,3 1 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; [email protected] 2 Department of Epidemiology, Indiana University Fairbanks School of Public Health, Indianapolis, IN 46202, USA 3 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-317-944-3966 Abstract: The use of clinical genetics evaluations and testing for infants with congenital heart defects (CHDs) is subject to practice variation. This single-institution cross-sectional study of all inpatient infants with severe CHDs evaluated 440 patients using a cardiovascular genetics service (2014–2019). In total, 376 (85.5%) had chromosome microarray (CMA), of which 55 (14.6%) were diagnostic in syndromic (N = 35) or isolated (N = 20) presentations. Genetic diagnoses were made in all CHD classes. Diagnostic yield was higher in syndromic appearing infants, but geneticists’ dysmorphology exams lacked complete sensitivity and 6.5% of isolated CHD cases had diagnostic CMA. Interestingly, diagnostic results (15.8%) in left ventricular outflow tract obstruction (LVOTO) defects occurred most Citation: Helm, B.M.; Landis, B.J.; often in patients with isolated CHD. Geneticists’ evaluations were particularly important for second- Ware, S.M. Genetic Evaluation of Inpatient Neonatal and Infantile tier molecular testing (10.5% test-specific yield), bringing the overall genetic testing yield to 17%. -
The Clark Phase-Able Sample Size Problem: Long-Range Phasing and Loss of Heterozygosity in GWAS
The Clark Phase-able Sample Size Problem: Long-Range Phasing and Loss of Heterozygosity in GWAS Bjarni V. Halld´orsson1,3,4,,, Derek Aguiar1,2,,, Ryan Tarpine1,2,,, and Sorin Istrail1,2,, 1 Center for Computational Molecular Biology, Brown University [email protected] 2 Department of Computer Science, Brown University [email protected] 3 School of Science and Engineering, Reykjavik University 4 deCODE genetics Abstract. A phase transition is taking place today. The amount of data generated by genome resequencing technologies is so large that in some cases it is now less expensive to repeat the experiment than to store the information generated by the experiment. In the next few years it is quite possible that millions of Americans will have been genotyped. The question then arises of how to make the best use of this information and jointly estimate the haplotypes of all these individuals. The premise of the paper is that long shared genomic regions (or tracts) are unlikely unless the haplotypes are identical by descent (IBD), in contrast to short shared tracts which may be identical by state (IBS). Here we estimate for populations, using the US as a model, what sample size of genotyped individuals would be necessary to have sufficiently long shared haplotype regions (tracts) that are identical by descent (IBD), at a statistically significant level. These tracts can then be used as input for a Clark-like phasing method to obtain a complete phasing solution of the sample. We estimate in this paper that for a population like the US and about 1% of the people genotyped (approximately 2 million), tracts of about 200 SNPs long are shared between pairs of individuals IBD with high probability which assures the Clark method phasing success. -
The Frequency of Aneuploidy in Cultured Lymphocytes Is Correlated with Age and Gender but Not with Reproductive History
Am. J. Hum. Genet. 46:1101-11, 1990 The Frequency of Aneuploidy in Cultured Lymphocytes Is Correlated with Age and Gender but Not with Reproductive History Gregory R Nowinski,$* Daniel L. Van Dyke, * Barbara C. Tilley, * Gordon Jacobsen,* V. Ramesh Babu,* Maria J. Worsham,* Golder N. Wilsont and Lester Weiss* * Medical Genetics and Birth Defects Center, and Division of Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit; and tDepartment of Pediatrics, University of Texas Southwestern Medical Center, Dallas Summary The clinical significance of low numbers of aneuploid cells in routine cytogenetic studies of cultured lym- phocytes is not always clear. We compared the frequencies of chromosome loss and gain among five groups of subjects whose karyotypes were otherwise normal; these groups were (1) subjects studied because of multiple miscarriages, (2) parents of live borns with autosomal trisomy, (3) subjects studied because they had a relative with Down syndrome, (4) an age-matched control group of phenotypically normal adults studied for other reasons (e.g., parent of a dysmorphic child or member of a translocation family), and (5) other mostly younger and phenotypically abnormal subjects who could not be assigned to the first four groups (e.g., individuals with multiple congenital anomalies or mental retardation). No significant age, sex, or group effects were observed for autosomal loss (hypodiploidy) or gain (hyperdiploidy). Au- tosomal loss was inversely correlated with relative chromosome length, but autosomal gain was not. Sex- chromosome gain was significantly more frequent in females than in males, but sex-chromosome loss was not significantly different between the sexes. Significant age effects were observed for both gain and loss of sex chromosomes. -
Acta Nr. 4 2012.Qxd
Case Report doi: 10.4183/aeb.2012.627 A NEW CASE OF TETRASOMY X IN A 8 YEARS OLD GIRL V. Plaiasu1,*, D. Ochiana1, G. Motei1 , I. A. Anca2 1 IOMC Alfred Rusescu - Genetics Department, 2 IOMC Alfred Rusescu, University of Medicine and Pharmacy “Carol Davila” - Pediatrics Department, Bucharest, Romania Abstract Genetic counseling is recommended. Chromosomal aberrations can be Although no cure exists specifically for this generally classified in two main categories: condition, the treatment of the symptoms structural abnormalities (such as can be efficient. Individuals should undergo translocations, deletions or duplications) medical and psychological evaluations. and numerical changes or aneuploidy. Aneuploidies are considered the most Key words: 48,XXXX, polysomy, frequent chromosomal defects occurring in mental deficiency, learning disabilities, humans and the leading cause of mild phenotype, genetic counseling. miscarriage and congenital birth defects. Here we present the case of an 8-year old girl with remarkable prenatal history, low birth weight and length associated with INTRODUCTION increased height in early childhood and developmental delay. On chromosomal Polysomies such as XXXX, XXYY, analysis a rare form of aneuploidy involving XYYY, XXXY, XXXXX, XXXXY are the sex chromosomes has been found in all very rare chromosomal defects. cells: 48, XXXX. Tetrasomy X (48,XXXX) Tetrasomy X (48,XXXX) is a sex is a sex chromosome aneuploidy condition chromosome aneuploidy condition in in which females have two extra X which females have two extra X chromosomes compared to the 46,XX chromosomes compared to the 46,XX karyotype in typical females. There is karyotype in typical females. The first two significant phenotypical variability for females with 48,XXXX have been tetrasomy X syndrome and many cases described by Carr et al.