DOCSLIB.ORG

Bainbridge-Ropers Syndrome (BRPS) (ASXL3 ‘Loss of Function’)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Bainbridge-Ropers Syndrome (BRPS) (ASXL3 ‘Loss of Function’) Bainbridge-Ropers syndrome (BRPS) (ASXL3 ‘loss of function’) rarechromo.org This guide is designed to help families and healthcare professionals looking after people affected by Bainbridge-Ropers Syndrome (BRPS). It contains information about the cause, the ways in which it can affect people and suggestions about the help and management that can benefit people with this syndrome. It also contains details about support groups and further information that families can access. What is Bainbridge-Ropers syndrome? Bainbridge-Ropers syndrome (BRPS) is a rare genetic condition that results from a change in function of a gene called ASXL3. The syndrome is named Bainbridge-Ropers after two researchers who first published the association of changes in the ASXL3 gene with specific characteristics and difficulties observed in some children (Bainbridge 2013). ASXL is an abbreviation of ‘Additional Sex Combs Like’ which is the name of a gene first identified in fruit flies (commonly used in genetic studies), hence the unusual name. What are genes? Genes are the ‘instructions’ that our bodies use for many functions including the control of growth and development. They are made from a complex structure called DNA. DNA, and hence genes, can be described as a sequence of letters but unlike an alphabet, the sequence (or code) only uses 4 letters (G, A, T, C). DNA sequences are incredibly long and include all the information for the thousands of genes included in our ‘genome’. However, they need to fit inside the microscopic cells from which our bodies are made. DNA is hence tightly compacted into organized structures called chromosomes. Most of our cells normally contain 46 chromosomes. We usually inherit 23 chromosomes from our mother and 23 from our father to make our very own unique ‘instruction manual’ containing two copies of most genes. The majority of important genes code for proteins. Genes can be described as carrying instructions for our cells and proteins carry out specific tasks. What genetic changes cause Bainbridge-Ropers syndrome? There are many different changes that can occur in the coding sequence of the ASXL3 gene, they are commonly called ‘variants’ or ’mutations’. Some will result in the production of no or very small amounts of a shorter (truncated) protein, these are named ‘loss of function (LOF) truncating mutations’. LOF mutations are thought to be responsible for BRPS, a deletion of the entire ASXL3 gene may also cause a similar outcome. Mutations in ASXL3 have also been identified that cause a change in the functional protein but do not cause BRPS or any obvious outcome, as we understand it at present. Most mutations are found in one copy of the ASXL3 gene, and most people will also have a second fully functional copy of ASXL3. It is expected then that half the amount of unaffected ASXL3 protein would be produced. 2 The information in this guide is drawn from clinical data, publications in the medical literature and information from Unique members. Publications used for this guide include: Bainbridge 2013, Dinwiddie 2013, Srivastava 2014, Hori 2016 and Kuechler 2017, Balasubramanian 2017, Koboldt 2018 and and Verhoeven 2018. Original articles and/or abstracts can be found on the internet in PubMed (http://www.ncbi.nlm. nih.gov/pubmed). If you wish, you can obtain most articles from Unique. What does ASXL3 do? The ASXL3 gene codes for the ASXL3 protein which is known to be involved in controlling the production of other proteins from other genes. Not all the functions of the ASXL3 gene/protein are currently known but knowledge of ASXL3 and its functions will improve over the years with further research. The ASXL3 gene is known to instruct different cells in different organs at different stages of development, changes to this gene can therefore affect different parts of the body in different ways. Perhaps the most important role of ASXL3 is in the brain during early development. It is possible that if a mutation occurred later in development, the time at which the mutation arose may influence a child’s outcome. Why did this happen and can it happen again? Bainbridge-Ropers syndrome is thought to be most often caused by a new (de novo (dn)) ‘mutation’ in the ASXL3 gene which randomly occurred in the formation of the egg or sperm from which a child is conceived. Mutations in ASXL3 that cause BRPS are not often inherited from a parent, the risk of having another child with this syndrome is therefore thought to be very low. When a child is identified as having an ASXL3 mutation, both parents are usually offered a genetic test to establish possible inheritance. Although it is rare, it is possible for an adult with BRPS, to pass on their genetic variation to their child. This has been reported in a family where the parent has a much milder outcome to their child (Dr Balasubramanian personal communication). Where neither parent is found to have an ASXL3 mutation, following a DNA test from a blood sample, it is unlikely that they will have another child with an ASXL3 mutation or any other chromosome disorder. However, very rarely (less than 1% of the time), both parents can be found to have unaffected chromosomes, but a few of their egg or sperm cells can carry an ASXL3 mutation. This is called germline mosaicism and it means that parents whose chromosomes appear normal when their blood is tested can have more than one child with the mutation. Although this is incredibly rare, one such incidence has been reported in the medical literature (Koboldt 2018) and Unique has a family member with two children with BRPS. It is for these reasons, parental testing and genetic counselling are recommended for families wanting to have further children. It is important to emphasize that this is nobody’s fault. There is nothing either parent did before, during or after the pregnancy that could have caused this genetic change. 3 How common is BainbridgeRopers Syndrome? Bainbridge-Ropers syndrome was first described in 2013 and since then about 30 children have been described in the medical literature as having a mutation in one of their two copies of the ASXL3 gene. However, many more children, are known to have Bainbridge-Ropers Syndrome, currently (2018) an estimated 200 are known worldwide and many more have yet to be diagnosed. The ASXL3 support group (BRSfamilies) currently has approximately 180 families registered with a child with an ASXL3 variant. Genetic testing was once a complicated, costly and time consuming process and was normally only offered to children with severe difficulties for which an explanation could not be found. Relatively recently there have been major advances in technology and cost efficiency, that have enabled a more prolific use of genetic testing, and children with a ‘spectrum’ of difficulties are more frequently identified with similar genetic changes. Following on from initial research findings where the majority of children with BRPS have quite severe outcomes, children with ASXL3 LOF mutations and milder difficulties are now being identified (Dr Balasubramanian personal communication). What features and symptoms do people with BRPS have? As with many genetic conditions, children with Bainbridge-Ropers syndrome can have a range of symptoms. As more children are diagnosed, and information is shared, the range of difficulties and the likelihood of a child having these features will become more clear. At the moment (2018), most children who have been given a diagnosis of BRPS have been identified as having moderate to severe intellectual disability, limited or absent speech, autism or autistic traits and significant feeding difficulties when young. A number of children are also identified as having low muscle tone (hypotonia) or being ‘floppy’ as a baby or young child. Other less frequently reported features have been identified and will be described in this guide. Common features: Intellectual disability Autism spectrum disorder or autistic like behaviour Feeding difficulties as a baby and in early childhood Developmental delay Postnatal growth problems Speech and language difficulties or absent speech Hypotonia (low muscle tone/floppiness) Sleep disturbance Specific facial features 4 Pregnancy and Birth The majority of pregnancies of children with BRPS reported so far have progressed to term (38-42 weeks) and have been mostly unremarkable. There are a few reports of poor foetal growth in the womb which is commonly referred to as IUGR (intrauterine growth restriction). A caesarean section was performed for about half of the births reported to date mainly due to the baby being in a breech position (when a baby is not positioned in a way that allows the head to move first through the birth canal). A third of babies reported in the medical literature were admitted to a neonatal unit following birth due to respiratory difficulties or apnoea (pauses in breathing or shallow breathing during sleep). Overall, children with BRPS have been reported to have birth weights within the normal range, but few Unique families have reported a low 2 months birth weight for their BRPS child. Feeding and Growth Poor growth after birth has commonly been reported and babies may be described as ‘failure to thrive’. This may be due to feeding difficulties and possibly poor appetite, babies may also have a poor suck or swallow reflex related to hypotonia. Babies with BRPS are commonly reported as having gastro-oesophageal reflux or vomiting. For some, the use of medications to help control reflux has been beneficial, others have required nasogastric tube feeding (where a tube is placed through the nose into the stomach) and a few have required a surgical intervention called fundoplication (to strengthen a muscle so stomach content is less likely to travel back into the food pipe).
Load more

Recommended publications
  • De Novo Frameshift Mutation in ASXL3 in a Patient with Global Developmental Delay, Microcephaly, and Craniofacial Anomalies
    Children's Mercy Kansas City SHARE @ Children's Mercy Manuscripts, Articles, Book Chapters and Other Papers 9-17-2013 De novo frameshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies. Darrell L. Dinwiddie Sarah E. Soden Children's Mercy Hospital Carol J. Saunders Children's Mercy Hospital Neil A. Miller Children's Mercy Hospital Emily G. Farrow Children's Mercy Hospital See next page for additional authors Follow this and additional works at: https://scholarlyexchange.childrensmercy.org/papers Part of the Medical Genetics Commons Recommended Citation Dinwiddie, D. L., Soden, S. E., Saunders, C. J., Miller, N. A., Farrow, E. G., Smith, L. D., Kingsmore, S. F. De novo frameshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies. BMC Med Genomics 6, 32-32 (2013). This Article is brought to you for free and open access by SHARE @ Children's Mercy. It has been accepted for inclusion in Manuscripts, Articles, Book Chapters and Other Papers by an authorized administrator of SHARE @ Children's Mercy. For more information, please contact [email protected]. Creator(s) Darrell L. Dinwiddie, Sarah E. Soden, Carol J. Saunders, Neil A. Miller, Emily G. Farrow, Laurie D. Smith, and Stephen F. Kingsmore This article is available at SHARE @ Children's Mercy: https://scholarlyexchange.childrensmercy.org/papers/1414 Dinwiddie et al. BMC Medical Genomics 2013, 6:32 http://www.biomedcentral.com/1755-8794/6/32 CASE REPORT Open Access De novo frameshift
    [Show full text]
  • Mechanisms Underlying Phenotypic Heterogeneity in Simplex Autism Spectrum Disorders
    Mechanisms Underlying Phenotypic Heterogeneity in Simplex Autism Spectrum Disorders Andrew H. Chiang Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2021 © 2021 Andrew H. Chiang All Rights Reserved Abstract Mechanisms Underlying Phenotypic Heterogeneity in Simplex Autism Spectrum Disorders Andrew H. Chiang Autism spectrum disorders (ASD) are a group of related neurodevelopmental diseases displaying significant genetic and phenotypic heterogeneity. Despite recent progress in ASD genetics, the nature of phenotypic heterogeneity across probands is not well understood. Notably, likely gene- disrupting (LGD) de novo mutations affecting the same gene often result in substantially different ASD phenotypes. We find that truncating mutations in a gene can result in a range of relatively mild decreases (15-30%) in gene expression due to nonsense-mediated decay (NMD), and show that more severe autism phenotypes are associated with greater decreases in expression. We also find that each gene with recurrent ASD mutations can be described by a parameter, phenotype dosage sensitivity (PDS), which characteriZes the relationship between changes in a gene’s dosage and changes in a given phenotype. Using simple linear models, we show that changes in gene dosage account for a substantial fraction of phenotypic variability in ASD. We further observe that LGD mutations affecting the same exon frequently lead to strikingly similar phenotypes in unrelated ASD probands. These patterns are observed for two independent proband cohorts and multiple important ASD-associated phenotypes. The observed phenotypic similarities are likely mediated by similar changes in gene dosage and similar perturbations to the relative expression of splicing isoforms.
    [Show full text]
  • ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and A
    Author Manuscript Published OnlineFirst on September 21, 2017; DOI: 10.1158/0008-5472.CAN-17-0570 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ASXL3 is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer Vivek Shukla1, Mahadev Rao1, Hongen Zhang2, Jeanette Beers3, Darawalee Wangsa2, Danny Wangsa2, Floryne O. Buishand2, Yonghong Wang2, Zhiya Yu5, Holly S. Stevenson2, Emily S. Reardon1, Kaitlin C. McLoughlin1, Andrew S. Kaufman1, Eden C. Payabyab1, Julie A. Hong1, Mary Zhang1, Sean Davis2, Daniel Edelman2, Guokai Chen3*, Markku M. Miettinen4, Nicholas P. Restifo5, Thomas Ried2, Paul A. Meltzer2, David S. Schrump1# 1Thoracic Epigenetics Section, Thoracic and Gastrointestinal Oncology Branch; 2Genetics Branch, 4Laboratory of Pathology, 5Surgery Branch, Center for Cancer Research, National Cancer Institute; 3NHLBI iPSC Core, National Institutes of Health, Bethesda, MD * Present address: University of Macau, China. Running Title: ASXL3, Lu-iPSC and SCLC Keywords: iPSC, ASXL3, lung cancer, small cell lung cancer, epigenetics Financial Support: This work was supported by NCI Intramural grants ZIA BC 011122 (to D.S. Schrump) and ZIA BC 011418 (to D.S. Schrump), and the Stephen J. Solarz Memorial Fund (to D.S. Schrump). #Corresponding Author David S. Schrump, MD, MBA, FACS Thoracic and GI Oncology Branch, CCR/NCI Building 10; 4-3942, 10 Center Drive, MSC 1201 Bethesda, MD 20892-1201 Tel: 301-496-2128 Fax: 301-451-6934 Email: [email protected] 1 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 21, 2017; DOI: 10.1158/0008-5472.CAN-17-0570 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
    [Show full text]
  • Combinatorial Strategies Using CRISPR/Cas9 for Gene Mutagenesis in Adult Mice
    Combinatorial strategies using CRISPR/Cas9 for gene mutagenesis in adult mice Avery C. Hunker A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2019 Reading Committee: Larry S. Zweifel, Chair Sheri J. Mizumori G. Stanley McKnight Program Authorized to Offer Degree: Pharmacology 2 © Copyright 2019 Avery C. Hunker 3 University of Washington ABSTRACT Combinatorial strategies using CRISPR/Cas9 for gene mutagenesis in adult mice Avery C. Hunker Chair of the Supervisory Committee: Larry Zweifel Department of Pharmacology A major challenge to understanding how genes modulate complex behaviors is the inability to restrict genetic manipulations to defined cell populations or circuits. To circumvent this, we created a simple strategy for limiting gene knockout to specific cell populations using a viral-mediated, conditional CRISPR/SaCas9 system in combination with intersectional genetic strategies. A small single guide RNA (sgRNA) directs Staphylococcus aureus CRISPR-associated protein (SaCas9) to unique sites on DNA in a Cre-dependent manner resulting in double strand breaks and gene mutagenesis in vivo. To validate this technique we targeted nine different genes of diverse function in distinct cell types in mice and performed an array of analyses to confirm gene mutagenesis and subsequent protein loss, including IHC, cell-type specific DNA sequencing, electrophysiology, Western blots, and behavior. We show that these vectors are as efficient as conventional conditional gene knockout and provide a viable alternative to complex genetic crosses. This strategy provides additional benefits of 4 targeting gene mutagenesis to cell types previously difficult to isolate, and the ability to target genes in specific neural projections for gene inactivation.
    [Show full text]
  • Castration Delays Epigenetic Aging and Feminizes DNA
    RESEARCH ARTICLE Castration delays epigenetic aging and feminizes DNA methylation at androgen- regulated loci Victoria J Sugrue1, Joseph Alan Zoller2, Pritika Narayan3, Ake T Lu4, Oscar J Ortega-Recalde1, Matthew J Grant3, C Simon Bawden5, Skye R Rudiger5, Amin Haghani4, Donna M Bond1, Reuben R Hore6, Michael Garratt1, Karen E Sears7, Nan Wang8, Xiangdong William Yang8,9, Russell G Snell3, Timothy A Hore1†*, Steve Horvath4†* 1Department of Anatomy, University of Otago, Dunedin, New Zealand; 2Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, United States; 3Applied Translational Genetics Group, School of Biological Sciences, Centre for Brain Research, The University of Auckland, Auckland, New Zealand; 4Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; 5Livestock and Farming Systems, South Australian Research and Development Institute, Roseworthy, Australia; 6Blackstone Hill Station, Becks, RD2, Omakau, New Zealand; 7Department of Ecology and Evolutionary Biology, UCLA, Los Angeles, United States; 8Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, United States; 9Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, United States *For correspondence: Abstract In mammals, females generally live longer than males. Nevertheless, the mechanisms [email protected] (TAH); underpinning sex-dependent longevity are currently unclear. Epigenetic clocks are powerful [email protected] (SH) biological biomarkers capable of precisely estimating chronological age and identifying novel †These authors contributed factors influencing the aging rate using only DNA methylation data. In this study, we developed the equally to this work first epigenetic clock for domesticated sheep (Ovis aries), which can predict chronological age with a median absolute error of 5.1 months.
    [Show full text]
  • Chromosome 18 Gene Dosage Map 2.0
    Human Genetics (2018) 137:961–970 https://doi.org/10.1007/s00439-018-1960-6 ORIGINAL INVESTIGATION Chromosome 18 gene dosage map 2.0 Jannine D. Cody1,2 · Patricia Heard1 · David Rupert1 · Minire Hasi‑Zogaj1 · Annice Hill1 · Courtney Sebold1 · Daniel E. Hale1,3 Received: 9 August 2018 / Accepted: 14 November 2018 / Published online: 17 November 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract In 2009, we described the first generation of the chromosome 18 gene dosage maps. This tool included the annotation of each gene as well as each phenotype associated region. The goal of these annotated genetic maps is to provide clinicians with a tool to appreciate the potential clinical impact of a chromosome 18 deletion or duplication. These maps are continually updated with the most recent and relevant data regarding chromosome 18. Over the course of the past decade, there have also been advances in our understanding of the molecular mechanisms underpinning genetic disease. Therefore, we have updated the maps to more accurately reflect this knowledge. Our Gene Dosage Map 2.0 has expanded from the gene and phenotype maps to also include a pair of maps specific to hemizygosity and suprazygosity. Moreover, we have revamped our classification from mechanistic definitions (e.g., haplosufficient, haploinsufficient) to clinically oriented classifications (e.g., risk factor, conditional, low penetrance, causal). This creates a map with gradient of classifications that more accurately represents the spectrum between the two poles of pathogenic and benign. While the data included in this manuscript are specific to chro- mosome 18, they may serve as a clinically relevant model that can be applied to the rest of the genome.
    [Show full text]
  • A Genomic Approach to Delineating the Occurrence of Scoliosis in Arthrogryposis Multiplex Congenita
    G C A T T A C G G C A T genes Article A Genomic Approach to Delineating the Occurrence of Scoliosis in Arthrogryposis Multiplex Congenita Xenia Latypova 1, Stefan Giovanni Creadore 2, Noémi Dahan-Oliel 3,4, Anxhela Gjyshi Gustafson 2, Steven Wei-Hung Hwang 5, Tanya Bedard 6, Kamran Shazand 2, Harold J. P. van Bosse 5 , Philip F. Giampietro 7,* and Klaus Dieterich 8,* 1 Grenoble Institut Neurosciences, Université Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, 38000 Grenoble, France; [email protected] 2 Shriners Hospitals for Children Headquarters, Tampa, FL 33607, USA; [email protected] (S.G.C.); [email protected] (A.G.G.); [email protected] (K.S.) 3 Shriners Hospitals for Children, Montreal, QC H4A 0A9, Canada; [email protected] 4 School of Physical & Occupational Therapy, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3G 2M1, Canada 5 Shriners Hospitals for Children, Philadelphia, PA 19140, USA; [email protected] (S.W.-H.H.); [email protected] (H.J.P.v.B.) 6 Alberta Congenital Anomalies Surveillance System, Alberta Health Services, Edmonton, AB T5J 3E4, Canada; [email protected] 7 Department of Pediatrics, University of Illinois-Chicago, Chicago, IL 60607, USA 8 Institut of Advanced Biosciences, Université Grenoble Alpes, Inserm, U1209, CHU Grenoble Alpes, 38000 Grenoble, France * Correspondence: [email protected] (P.F.G.); [email protected] (K.D.) Citation: Latypova, X.; Creadore, S.G.; Dahan-Oliel, N.; Gustafson, Abstract: Arthrogryposis multiplex congenita (AMC) describes a group of conditions characterized A.G.; Wei-Hung Hwang, S.; Bedard, by the presence of non-progressive congenital contractures in multiple body areas.
    [Show full text]
  • Novel Splicing Mutation in B3GAT3 Associated with Short Stature, GH Deficiency, Hypoglycaemia, Developmental Delay, and Multiple Congenital Anomalies
    Hindawi Case Reports in Genetics Volume 2017, Article ID 3941483, 5 pages https://doi.org/10.1155/2017/3941483 Case Report Novel Splicing Mutation in B3GAT3 Associated with Short Stature, GH Deficiency, Hypoglycaemia, Developmental Delay, and Multiple Congenital Anomalies Samuel Bloor,1 Dinesh Giri,2,3 Mohammed Didi,3 and Senthil Senniappan2,3 1 School of Life Sciences, University of Liverpool, Liverpool, UK 2Institute of Child Health, University of Liverpool, Liverpool, UK 3Department of Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK Correspondence should be addressed to Senthil Senniappan; [email protected] Received 18 August 2017; Revised 31 October 2017; Accepted 7 November 2017; Published 28 November 2017 Academic Editor: Yoshiyuki Ban Copyright © 2017 Samuel Bloor et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. B3GAT3, encoding -1,3-glucuronyltransferase 3, has an important role in proteoglycan biosynthesis. Homozygous B3GAT3 mutations have been associated with short stature, skeletal deformities, and congenital heart defects. We describe for the first time a novel heterozygous splice site mutation in B3GAT3 contributing to severe short stature, growth hormone (GH) deficiency, recurrent ketotic hypoglycaemia, facial dysmorphism, and congenital heart defects. A female infant, born at 34 weeks’ gestation to nonconsanguineous Caucasian parents with a birth weight of 1.9 kg, was noted to have cloacal abnormality, ventricular septal defect, pulmonary stenosis, and congenital sensorineural deafness. At 4 years of age, she was diagnosed with GH deficiency due to her short stature (height < 2.5 SD).
    [Show full text]
  • Content Based Search in Gene Expression Databases and a Meta-Analysis of Host Responses to Infection
    Content Based Search in Gene Expression Databases and a Meta-analysis of Host Responses to Infection A Thesis Submitted to the Faculty of Drexel University by Francis X. Bell in partial fulfillment of the requirements for the degree of Doctor of Philosophy November 2015 c Copyright 2015 Francis X. Bell. All Rights Reserved. ii Acknowledgments I would like to acknowledge and thank my advisor, Dr. Ahmet Sacan. Without his advice, support, and patience I would not have been able to accomplish all that I have. I would also like to thank my committee members and the Biomed Faculty that have guided me. I would like to give a special thanks for the members of the bioinformatics lab, in particular the members of the Sacan lab: Rehman Qureshi, Daisy Heng Yang, April Chunyu Zhao, and Yiqian Zhou. Thank you for creating a pleasant and friendly environment in the lab. I give the members of my family my sincerest gratitude for all that they have done for me. I cannot begin to repay my parents for their sacrifices. I am eternally grateful for everything they have done. The support of my sisters and their encouragement gave me the strength to persevere to the end. iii Table of Contents LIST OF TABLES.......................................................................... vii LIST OF FIGURES ........................................................................ xiv ABSTRACT ................................................................................ xvii 1. A BRIEF INTRODUCTION TO GENE EXPRESSION............................. 1 1.1 Central Dogma of Molecular Biology........................................... 1 1.1.1 Basic Transfers .......................................................... 1 1.1.2 Uncommon Transfers ................................................... 3 1.2 Gene Expression ................................................................. 4 1.2.1 Estimating Gene Expression ............................................ 4 1.2.2 DNA Microarrays ......................................................
    [Show full text]
  • Differential and Spatial Expression Meta-Analysis of Genes Identified in Genome-Wide Association Studies of Depression
    bioRxiv preprint doi: https://doi.org/10.1101/2020.03.27.012435; this version posted May 13, 2020. 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-NC-ND 4.0 International license. Differential and spatial expression meta-analysis of genes identified in genome-wide association studies of depression Running title: Expression patterns of depression risk genes 1,2,3 3 1,2,4,5 1,2,3,4 Wennie Wu ,​ Derek Howard ,​ Etienne Sibille ,​ Leon French ​ ​ ​ ​ 1. Institute for Medical Science, University of Toronto, Toronto, Canada 2. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada 3. Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada 4. Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada 5. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada Corresponding author: Leon French, Centre for Addiction and Mental Health, Toronto, Ontario, Canada, M5T 1R8. [email protected] Abstract Major depressive disorder (MDD) is the most prevalent psychiatric disorder worldwide and affects individuals of all ages. It causes significant psychosocial impairments and is a major cause of disability. A recent consortium study identified 102 genetic variants and 269 genes associated with depression. To provide targets for future depression research, we prioritized these recently identified genes using expression data. We examined differential expression of these genes in three studies that profiled gene expression of MDD cases and controls across multiple brain regions.
    [Show full text]
  • Recurrent De Novo Mutations in Neurodevelopmental Disorders: Properties and Clinical Implications Amy B
    Wilfert et al. Genome Medicine (2017) 9:101 DOI 10.1186/s13073-017-0498-x REVIEW Open Access Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications Amy B. Wilfert1†, Arvis Sulovari1†, Tychele N. Turner1, Bradley P. Coe1 and Evan E. Eichler1,2* Abstract Next-generation sequencing (NGS) is now more accessible to clinicians and researchers. As a result, our understanding of the genetics of neurodevelopmental disorders (NDDs) has rapidly advanced over the past few years. NGS has led to the discovery of new NDD genes with an excess of recurrent de novo mutations (DNMs) when compared to controls. Development of large-scale databases of normal and disease variation has given rise to metrics exploring the relative tolerance of individual genes to human mutation. Genetic etiology and diagnosis rates have improved, which have led to the discovery of new pathways and tissue types relevant to NDDs. In this review, we highlight several key findings based on the discovery of recurrent DNMs ranging from copy number variants to point mutations. We explore biases and patterns of DNM enrichment and the role of mosaicism and secondary mutations in variable expressivity. We discuss the benefit of whole-genome sequencing (WGS) over whole-exome sequencing (WES) to understand more complex, multifactorial cases of NDD and explain how this improved understanding aids diagnosis and management of these disorders. Comprehensive assessment of the DNM landscape across the genome using WGS and other technologies will lead to the development of novel functional and bioinformatics approaches to interpret DNMs and drive new insights into NDD biology.
    [Show full text]
  • Mutation Load Estimation Model As a Predictor of the Response to Cancer Immunotherapy
    www.nature.com/npjgenmed ARTICLE OPEN Mutation load estimation model as a predictor of the response to cancer immunotherapy Guan-Yi Lyu1, Yu-Hsuan Yeh2, Yi-Chen Yeh3,4 and Yu-Chao Wang1,5 The determination of the mutation load, a total number of nonsynonymous point mutations, by whole-exome sequencing was shown to be useful in predicting the treatment responses to cancer immunotherapy. However, this technique is expensive and time-consuming, which hampers its application in clinical practice. Therefore, the objective of this study was to construct a mutation load estimation model for lung adenocarcinoma, using a small set of genes, as a predictor of the immunotherapy treatment response. Using the somatic mutation data downloaded from The Cancer Genome Atlas (TCGA) database, a computational framework was developed. The estimation model consisted of only 24 genes, used to estimate the mutation load in the independent validation cohort precisely (R2 = 0.7626). Additionally, the estimated mutation load can be used to identify the patients with durable clinical benefits, with 85% sensitivity, 93% specificity, and 89% accuracy, indicating that the model can serve as a predictive biomarker for cancer immunotherapy treatment response. Furthermore, our analyses demonstrated the necessity of the cancer-specific models by the constructed melanoma and colorectal models. Since most genes in the lung adenocarcinoma model are not currently included in the sequencing panels, a customized targeted sequencing panel can be designed with the selected model genes to assess the mutation load, instead of whole-exome sequencing or the currently used panel-based methods. Consequently, the cost and time required for the assessment of mutation load may be considerably decreased, which indicates that the presented model is a more cost-effective approach to cancer immunotherapy response prediction in clinical practice.
    [Show full text]