DOCSLIB.ORG

Facioscapulohumeral Muscular Dystrophy (FSHD) Molecular Diagnosis: from Traditional Technology to the NGS Era

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Facioscapulohumeral Muscular Dystrophy (FSHD) Molecular Diagnosis: from Traditional Technology to the NGS Era neurogenetics (2019) 20:57–64 https://doi.org/10.1007/s10048-019-00575-4 REVIEW ARTICLE Facioscapulohumeral muscular dystrophy (FSHD) molecular diagnosis: from traditional technology to the NGS era Stefania Zampatti1 & Luca Colantoni1 & Claudia Strafella2 & Rosaria Maria Galota1 & Valerio Caputo2 & Giulia Campoli1 & Giulia Pagliaroli1 & Stefania Carboni1 & Julia Mela1 & Cristina Peconi1 & Stefano Gambardella3 & Raffaella Cascella1,4 & Emiliano Giardina1,2 Received: 14 January 2019 /Accepted: 17 March 2019 /Published online: 25 March 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Facioscapulohumeral muscular dystrophy (FSHD) is a genetic neuromuscular disorder which mainly affects the muscles of the face, shoulder, and upper arms. FSHD is generally associated with the contraction of D4Z4 macrosatellite repeats on 4q35 chromosome or mutations in SMCHD1, which are responsible of the toxic expression of DUX4 in muscle tissue. Despite the recent application of NGS techniques in the clinical practice, the molecular diagnosis of FSHD is still performed with dated techniques such as Southern blotting. The diagnosis of FSHD requires therefore specific skills on both modern and less modern analytical protocols. Considering that clinical and molecular diagnosis of FSHD is challenging, it is not surprising that only few laboratories offer a comprehensive characterization of FSHD, which requires the education of professionals on traditional techniques even in the era of NGS. In conclusion, the study of FSHD provides an excellent example of using classical and modern molecular technologies which are equally necessary for the analysis of DNA repetitive traits associated with specific disorders. Keywords FSHD . D4Z4 contraction . SMCHD1 . Genetic counseling . Genetic test Introduction array of tandemly repeated units known as D4Z4. However, approximately 5% of patients display the typical disease phe- Facioscapulohumeral muscular dystrophy (FSHD, OMIM no. notype without carrying the D4Z4 contraction. This alterna- 158900) is the third most common hereditary myopathy, after tive form is termed FSHD2 and it has been associated with Duchenne dystrophy and myotonic dystrophy [1]. It has been pathogenetic mutations in Structural Maintenance of estimated to affect 1 in 8333 people worldwide [2]. Linkage Chromosomes Flexible Hinge Domain-Containing 1 analysis allowed the identification of the FSHD genetic locus (SMCHD1, 18p11.32) and DNA Methyltransferase 3 Beta on 4q35 chromosome [3]. The classical form of the disease (DNMT3B, 20q11.21) genes [4]. Although two distinct forms (referred to as FSHD1), in fact, has been associated with DNA of the disease (FSHD1 and FSHD2) have been described, rearrangements (contraction) in this region, consisting of an recent literature indicated that FSHD2-associated genes can also act as disease modifiers in FSHD1, rising the need for testing FSHD2 genes even in FSHD1 patients [3, 4]. * Raffaella Cascella The molecular diagnosis of FSHD1 is still based on tradi- [email protected] tional methods as Southern blotting that is expensive and labor intensive and requires large amounts of DNA. Several efforts 1 Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, have been made to set up alternative molecular methods, such via Ardeatina 354, 00142 Rome, Italy as molecular combing (MC) [5]. On the other hand, charac- 2 Department of Biomedicine and Prevention, Tor Vergata University, terization of FSHD2-related genes is made either by tradition- via Montpellier 1, 00133 Rome, Italy al or modern technologies (direct sequencing and NGS, re- 3 IRCCS Neuromed, via Atinense, 18, 86077 Pozzilli, Italy spectively) which allow high-throughput, less expensive, 4 Department of Biomedical Sciences, Catholic University Our Lady and reliable results. In this context, prominent attention should of Good Counsel, Rruga Dritan Hoxha, 1000 Tirana, Albania be given to the training of biologists and laboratory 58 Neurogenetics (2019) 20:57–64 technicians which should properly know not only the latest Although some severity markers have been recently de- but also the oldest technologies available to perform molecu- scribed, in most of the cases, the prognosis of the disease is lar diagnosis of peculiar disorders. unpredictable [10]. Sudden and dramatic worsening of the disease can occur after long periods of stable conditions. In addition, the clinical spectrum is widely variable among unre- Clinical features lated patients, including subjects with slight muscle weakness, who are unaware of being affected, as well as patients who are FSHD is a slowly progressive muscular dystrophy that typi- wheelchair-dependent [8]. This variability in disease clinical cally involves facial and shoulder muscles. The clinical course expression has been exemplified by a study on monozygotic of the disease can be highly variable, alternating stable and male twins, who carry the same genetic mutation but are af- worse conditions. The transmission pattern generally follows fected by FSHD at dramatically different extents [4]. Before an autosomal dominant pattern, although reduced penetrance the advent of molecular diagnosis, penetrance of FSHD was and variable expressivity complicate the identification of af- evaluated considering the clinical examination of patients at fected subjects within families [1]. In addition, up to 30% of risk and their age, resulting to be between 83 and 95% at cases are due to de novo mutations and, approximately half of 20 years of age [11]. However, a higher penetrance of the them, result from a post-zygotic mutation leading to mosai- disease has been reported in males compared to females, cism [4, 6]. The onset is usually between 6 and 20 years, who appeared to be mostly asymptomatic or minimally affect- suddenly in the adulthood. In the early stage of the disease, ed [7]. Recently, a prospective cross-sectional study reported the muscle involvement can be asymmetrical, and the weak- the age of onset of FSHD as a severity marker. Patients with an ness is so slight and slowly progressive that many cases re- early-onset FSHD (observed in 7–15% of all FSHD cases) main subclinical for several years. Generally, the first signs of have been found to experience a more severe and progressive the disease include difficulties in raising the arms over the disease with 57% patients being dependent on wheelchair head and scapular winging. Facial weakness has also been compared to 20–30% of classical FSHD cases. In addition, observed at the initial clinical stage of the disease and, in some age at onset has also been described as a prognostic marker cases, many years before the diagnosis. The involvement of in relation to the frequency of systemic complications [10]. facial muscles is generally underestimated because of the little impact on activities of daily living. The affected facial muscles are the orbicularis oculi, the zygomaticus, and the orbicularis Genetic aspects of FSHD1 oris which appear weak and thin. Patients are therefore unable to firmly close the eyes, to inflate cheeks, and to whistle. FSHD1 has been associated with DNA rearrangements Masticatory, lingual, and extraocular muscles are not involved (contraction) in a polymorphic region known as D4Z4 in FSHD [4]. The scapular girdle is the most involved region: (4q35) that is characterized by an array of tandemly repeated trapezius and pectoral muscles at the initial stage; the units extending for 3.3 kb. In normal conditions, the D4Z4 sternocleidomastoid, serratus magnus, rhomboid, erector array varies from 10 to 100 repeated units (RU), whereas spinae, latissimus dorsi later on; and ultimately, the deltoid FSHD patients have less than 10 RU [12]. The number of muscles [7]. Shoulder bones protrude out on the back, causing repeats can be determined by Southern blotting and hybridi- thereby scapular winging and clavicles sticking out and zation with the p13E-11 probe, which is able to recognize the rounded shoulders. Biceps are usually less involved than tri- D4Z4 region. However, the interpretation of the p13E-11 hy- ceps and brachioradialis muscles, although biceps can present bridization pattern is complicated by the fact that the probe a thinner proximal trait compared to the distal one (BPopeye^ can also recognize an additional locus on the 10q26 region effect) [8]. Pelvic girdle is involved some years after the onset that is nearly completely homologous to the 4q35 region (> of the disease, leading to pelvic muscle weakness and, subse- 98%) but it is not related to FSHD1 [4]. Moreover, the high quently, to mild lordosis and pelvic instability. Pretibial in- degree of sequence homology between 4qter and 10qter loci volvement leads to foot drop and gait instability [8]. facilitates inter-chromosomal exchange resulting in total and Beevor’s sign (the abnormal upward movement of the umbi- partial translocations. These translocation alleles are derive licus when the patient raises the head from a supine position) from ancient founding events but, indeed, complicate even is typical in the advanced stage of the disease, when up to 20% more the molecular diagnosis of the disease [6, 13]. of patients become wheelchair-dependent [7]. Cardiac in- Many studies suggested that D4Z4 contractions are not the volvement (rhythm disorders and cardiomegaly) is rare. only required conditions for FSHD manifestation [14]. The Although some studies have hypothesized anticipation phe- genomic architecture of the 4q35 region and its flanking re-
Load more

Recommended publications
  • Smchd1-Dependent and -Independent Pathways Determine Developmental Dynamics of Cpg Island Methylation on The
    Edinburgh Research Explorer Smchd1-Dependent and -Independent Pathways Determine Developmental Dynamics of CpG Island Methylation on the Inactive X Chromosome Citation for published version: Gendrel, AV, Apedaile, A, Coker, H, Termanis, A, Zvetkova, I, Godwin, J, Montana, G, Taylor, S, Giannoulatou, E, Heard, E, Stancheva, I & Brockdorff, N 2012, 'Smchd1-Dependent and -Independent Pathways Determine Developmental Dynamics of CpG Island Methylation on the Inactive X Chromosome', Developmental Cell, vol. 23, no. 2, pp. 265–279. https://doi.org/10.1016/j.devcel.2012.06.011 Digital Object Identifier (DOI): 10.1016/j.devcel.2012.06.011 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Developmental Cell General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 07. Oct. 2021 Developmental Cell Article Smchd1-Dependent and -Independent Pathways Determine Developmental Dynamics of CpG Island Methylation on the Inactive X Chromosome Anne-Valerie Gendrel,1,7,8 Anwyn Apedaile,3,8 Heather Coker,1 Ausma Termanis,4 Ilona Zvetkova,3,9 Jonathan Godwin,1 Y.
    [Show full text]
  • Genotype, Phenotype and Cancer: Role of Low Penetrance Genes and Environment in Tumour Susceptibility
    Genotype, phenotype and cancer: Role of low penetrance genes and environment in tumour susceptibility † ASHWIN KOTNIS, RAJIV SARIN and RITA MULHERKAR* Genetic Engineering, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410 208, India †Tata Memorial Hospital, Parel, Mumbai 400 012, India *Corresponding author (Fax, 91-22-27412892; Email, [email protected]) Role of heredity and lifestyle in sporadic cancers is well documented. Here we focus on the influence of low penetrance genes and habits, with emphasis on tobacco habit in causing head and neck cancers. Role of such gene-environment interaction can be well studied in individuals with multiple primary cancers. Thus such a bio- logical model may elucidate that cancer causation is not solely due to genetic determinism but also significantly relies on lifestyle of the individual. [Kotnis A, Sarin R and Mulherkar R 2005 Genotype, phenotype and cancer: Role of low penetrance genes and environment in tumour sus- ceptibility; J. Biosci. 30 93–102] 1. Introduction are chromosomal translocations which result in fusion proteins (e.g. bcr-abl fusion protein due to translocation Cancer has been a scourge on the human population for of abl gene to bcr locus in Chronic Myeloid Leukemia) many years. Although numerous advances have been made or apposition of one gene to the regulatory region of an- in prevention, diagnosis and treatment of the disease, it other gene (e.g. RET and NTRK1 in thyroid papillary carci- still continues to torment mankind. As is widely believed, noma), resulting in giving the cell a growth advantage. cancer is the result of many genetic and epigenetic changes These chromosomal translocations are common in lym- in a population of cells as well as in the surrounding phomas, leukemias and mesenchymal tumours (Futreal stroma and blood vessels.
    [Show full text]
  • VU Research Portal
    VU Research Portal Genetic architecture and behavioral analysis of attention and impulsivity Loos, M. 2012 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Loos, M. (2012). Genetic architecture and behavioral analysis of attention and impulsivity. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 28. Sep. 2021 Genetic architecture and behavioral analysis of attention and impulsivity Maarten Loos 1 About the thesis The work described in this thesis was performed at the Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands. This work was in part funded by the Dutch Neuro-Bsik Mouse Phenomics consortium. The Neuro-Bsik Mouse Phenomics consortium was supported by grant BSIK 03053 from SenterNovem (The Netherlands).
    [Show full text]
  • Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings
    G C A T T A C G G C A T genes Article Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings Jasleen Dhaliwal 1 , Ying Qiao 1,2, Kristina Calli 1,2, Sally Martell 1,2, Simone Race 3,4,5, Chieko Chijiwa 1,5, Armansa Glodjo 3,5, Steven Jones 1,6 , Evica Rajcan-Separovic 2,7, Stephen W. Scherer 4 and Suzanne Lewis 1,2,5,* 1 Department of Medical Genetics, University of British Columbia (UBC), Vancouver, BC V6H 3N1, Canada; [email protected] (J.D.); [email protected] (Y.Q.); [email protected] (K.C.); [email protected] (S.M.); [email protected] (C.C.); [email protected] (S.J.) 2 BC Children’s Hospital, Vancouver, BC V5Z 4H4, Canada; [email protected] 3 Department of Pediatrics, University of British Columbia (UBC), Vancouver, BC V6T 1Z7, Canada; [email protected] (S.R.); [email protected] (A.G.) 4 The Centre for Applied Genomics and McLaughlin Centre, Hospital for Sick Children and University of Toronto, Toronto, ON M5G 0A4, Canada; [email protected] 5 BC Children’s and Women’s Health Center, Vancouver, BC V6H 3N1, Canada 6 Michael Smith Genome Sciences Centre, Vancouver, BC V5Z 4S6, Canada 7 Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC V6T 1Z7, Canada * Correspondence: [email protected] Abstract: Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in Citation: Dhaliwal, J.; Qiao, Y.; Calli, children and shows high heritability.
    [Show full text]
  • Myopia in African Americans Is Significantly Linked to Chromosome 7P15.2-14.2
    Genetics Myopia in African Americans Is Significantly Linked to Chromosome 7p15.2-14.2 Claire L. Simpson,1,2,* Anthony M. Musolf,2,* Roberto Y. Cordero,1 Jennifer B. Cordero,1 Laura Portas,2 Federico Murgia,2 Deyana D. Lewis,2 Candace D. Middlebrooks,2 Elise B. Ciner,3 Joan E. Bailey-Wilson,1,† and Dwight Stambolian4,† 1Department of Genetics, Genomics and Informatics and Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, United States 2Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States 3The Pennsylvania College of Optometry at Salus University, Elkins Park, Pennsylvania, United States 4Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States Correspondence: Joan E. PURPOSE. The purpose of this study was to perform genetic linkage analysis and associ- Bailey-Wilson, NIH/NHGRI, 333 ation analysis on exome genotyping from highly aggregated African American families Cassell Drive, Suite 1200, Baltimore, with nonpathogenic myopia. African Americans are a particularly understudied popula- MD 21131, USA; tion with respect to myopia. [email protected]. METHODS. One hundred six African American families from the Philadelphia area with a CLS and AMM contributed equally to family history of myopia were genotyped using an Illumina ExomePlus array and merged this work and should be considered co-first authors. with previous microsatellite data. Myopia was initially measured in mean spherical equiv- JEB-W and DS contributed equally alent (MSE) and converted to a binary phenotype where individuals were identified as to this work and should be affected, unaffected, or unknown.
    [Show full text]
  • A Curated Gene List for Reporting Results of Newborn Genomic Sequencing
    © American College of Medical Genetics and Genomics ORIGINAL RESEARCH ARTICLE A curated gene list for reporting results of newborn genomic sequencing Ozge Ceyhan-Birsoy, PhD1,2,3, Kalotina Machini, PhD1,2,3, Matthew S. Lebo, PhD1,2,3, Tim W. Yu, MD3,4,5, Pankaj B. Agrawal, MD, MMSC3,4,6, Richard B. Parad, MD, MPH3,7, Ingrid A. Holm, MD, MPH3,4, Amy McGuire, PhD8, Robert C. Green, MD, MPH3,9,10, Alan H. Beggs, PhD3,4, Heidi L. Rehm, PhD1,2,3,10; for the BabySeq Project Purpose: Genomic sequencing (GS) for newborns may enable detec- of newborn GS (nGS), and used our curated list for the first 15 new- tion of conditions for which early knowledge can improve health out- borns sequenced in this project. comes. One of the major challenges hindering its broader application Results: Here, we present our curated list for 1,514 gene–disease is the time it takes to assess the clinical relevance of detected variants associations. Overall, 954 genes met our criteria for return in nGS. and the genes they impact so that disease risk is reported appropri- This reference list eliminated manual assessment for 41% of rare vari- ately. ants identified in 15 newborns. Methods: To facilitate rapid interpretation of GS results in new- Conclusion: Our list provides a resource that can assist in guiding borns, we curated a catalog of genes with putative pediatric relevance the interpretive scope of clinical GS for newborns and potentially for their validity based on the ClinGen clinical validity classification other populations. framework criteria, age of onset, penetrance, and mode of inheri- tance through systematic evaluation of published evidence.
    [Show full text]
  • Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility: Evidence Synthesis
    Evidence Synthesis Number 37 Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility: Evidence Synthesis Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract No. 290-02-0024 Task Order No. 2 Technical Support of the U.S. Preventive Services Task Force Prepared by: Oregon Evidence-based Practice Center Portland, Oregon Investigators Heidi D. Nelson, MD, MPH Laurie Hoyt Huffman, MS Rongwei Fu, PhD Emily L. Harris, PhD, MPH Miranda Walker, BA Christina Bougatsos, BS September 2005 This report may be used, in whole or in part, as the basis of the development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and access. The information helps health care decisionmakers—patients and clinicians, health system leaders, and policymakers—make more informed decisions and improve the quality of health care services. Preface The Agency for Healthcare Research and Quality (AHRQ) sponsors the development of Systematic Evidence Reviews (SERs) and Evidence Syntheses through its Evidence-based Practice Program. With guidance from the U.S.
    [Show full text]
  • The Nature and Significance of Behavioural Genetic Information
    Postprint This is a pre-copyedited, author-produced PDF of an article accepted for publication in Theoretical Medicine and Bioethics following peer review. The definitive publisher-authenticated version [Newson, A.J. (2004) “The nature and significance of behavioural genetic information.” Theoretical Medicine and Bioethics, 25: 89–111.] is available online at http://link.springer.com/article/10.1023/B:META.0000033764.50604.85 The nature and significance of behavioural genetic information Ainsley Newson BSc (Hons) PhD, 2004 Abstract In light of the human genome project, establishing the genetic aetiology of complex human diseases has become a research priority within Western medicine. However, in addition to the identification of disease genes, numerous research projects are also being undertaken to identify genes contributing to the development of human behavioural characteristics, such as cognitive ability and criminal tendency. The permissibility of this research is obviously controversial: will society benefit from this research, or will it adversely affect our conceptions of ourselves and each other? When assessing the permissibility of this research, it is important to consider the nature and deterministic significance of behavioural genetic information. Whilst to date there has been much discussion and debate about the properties of genetic information per se and genetic determinism, this has not been applied to behavioural genetic research and its ethical implications. Therefore, this paper elucidates how behavioural genetic information can be distinguished from different from other types of genetic and non-genetic information and also synthesises the determinative significance of genetic factors for the development of human behavioural traits. Undertaking this analysis enables the ethical issues raised by this research to be debated in an appropriate context and indicates that separate policy considerations are warranted.
    [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]
  • Guide to Interpreting Genomic Reports: a Genomics Toolkit
    Guide to Interpreting Genomic Reports: A Genomics Toolkit A guide to genomic test results for non-genetics providers Created by the Practitioner Education Working Group of the Clinical Sequencing Exploratory Research (CSER) Consortium Genomic Report Toolkit Authors Kelly East, MS, CGC, Wendy Chung MD, PhD, Kate Foreman, MS, CGC, Mari Gilmore, MS, CGC, Michele Gornick, PhD, Lucia Hindorff, PhD, Tia Kauffman, MPH, Donna Messersmith , PhD, Cindy Prows, MSN, APRN, CNS, Elena Stoffel, MD, Joon-Ho Yu, MPh, PhD and Sharon Plon, MD, PhD About this resource This resource was created by a team of genomic testing experts. It is designed to help non-geneticist healthcare providers to understand genomic medicine and genome sequencing. The CSER Consortium1 is an NIH-funded group exploring genomic testing in clinical settings. Acknowledgements This work was conducted as part of the Clinical Sequencing Exploratory Research (CSER) Consortium, grants U01 HG006485, U01 HG006485, U01 HG006546, U01 HG006492, UM1 HG007301, UM1 HG007292, UM1 HG006508, U01 HG006487, U01 HG006507, R01 HG006618, and U01 HG007307. Special thanks to Alexandria Wyatt and Hugo O’Campo for graphic design and layout, Jill Pope for technical editing, and the entire CSER Practitioner Education Working Group for their time, energy, and support in developing this resource. Contents 1 Introduction and Overview ................................................................ 3 2 Diagnostic Results Related to Patient Symptoms: Pathogenic and Likely Pathogenic Variants . 8 3 Uncertain Results
    [Show full text]
  • Autism Spectrum Disorders: an Updated Guide for Genetic Counseling Transtornos Do Espectro Autista: Um Guia Atualizado Para Aconselhamento Genético
    REVIEWING BASIC SCIENCES Autism spectrum disorders: an updated guide for genetic counseling Transtornos do espectro autista: um guia atualizado para aconselhamento genético Karina Griesi-Oliveira1, Andréa Laurato Sertié1 ABSTRACT desenvolvimento de novas ferramentas de diagnóstico molecular, Autism spectrum disorder is a complex and genetically heterogeneous tem mudado este cenário de forma substancial. Atualmente, estima- disorder, which has hampered the identification of the etiological se que, por meio de testes moleculares, é possível detectar uma factors in each patient and, consequently, the genetic counseling alteração genética potencialmente causal em cerca de 25% dos for families at risk. However, in the last decades, the remarkable casos. Considerando-se também a avaliação clínica, a história advances in the knowledge of genetic aspects of autism based on pré-natal e a investigação de outros aspectos fisiológicos, pode- genetic and molecular research, as well as the development of new se atribuir uma etiologia para aproximadamente 30 a 40% dos molecular diagnostic tools, have substantially changed this scenario. pacientes. Assim, em vista do conhecimento atual sobre a arquitetura Nowadays, it is estimated that using the currently available molecular genética do transtorno do espectro autista, que tem tornado o tests, a potential underlying genetic cause can be identified in nearly aconselhamento genético cada vez mais preciso, e dos potenciais 25% of cases. Combined with clinical assessment, prenatal history benefícios que a investigação etiológica pode trazer aos pacientes e evaluation and investigation of other physiological aspects, an familiares, tornam-se cada vez mais importantes os testes genéticos etiological explanation for the disease can be found for approximately moleculares.
    [Show full text]
  • A Quantitative Telomeric Chromatin Isolation Protocol Identifies Different Telomeric States
    ARTICLE Received 20 Aug 2013 | Accepted 31 Oct 2013 | Published 25 Nov 2013 DOI: 10.1038/ncomms3848 A quantitative telomeric chromatin isolation protocol identifies different telomeric states Larissa Grolimund1,2,*, Eric Aeby1,2,*, Romain Hamelin1,3, Florence Armand1,3, Diego Chiappe1,3, Marc Moniatte1,3 & Joachim Lingner1,2 Telomere composition changes during tumourigenesis, aging and in telomere syndromes in a poorly defined manner. Here we develop a quantitative telomeric chromatin isolation protocol (QTIP) for human cells, in which chromatin is cross-linked, immunopurified and analysed by mass spectrometry. QTIP involves stable isotope labelling by amino acids in cell culture (SILAC) to compare and identify quantitative differences in telomere protein com- position of cells from various states. With QTIP, we specifically enrich telomeric DNA and all shelterin components. We validate the method characterizing changes at dysfunctional tel- omeres, and identify and validate known, as well as novel telomere-associated polypeptides including all THO subunits, SMCHD1 and LRIF1. We apply QTIP to long and short telomeres and detect increased density of SMCHD1 and LRIF1 and increased association of the shel- terins TRF1, TIN2, TPP1 and POT1 with long telomeres. Our results validate QTIP to study telomeric states during normal development and in disease. 1 EPFL-Ecole Polytechnique Fe´de´rale de Lausanne, School of Life Sciences, CH-1015 Lausanne, Switzerland. 2 ISREC-Swiss Institute fro Experimental Cancer Research at EPFL, CH-1015 Lausanne, Switzerland. 3 Proteomics Core Facility at EPFL, CH-1015 Lausanne, Switzerland. * These authors contributed equally to this work. Correspondence and requests for materials should be addressed to J.L.
    [Show full text]