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Uniparental Disomy (UPD) in Clinical Genetics Thomas Liehr • UNIQUE

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Uniparental Disomy (UPD) in Clinical Genetics Thomas Liehr • UNIQUE Uniparental Disomy (UPD) in Clinical Genetics Thomas Liehr • UNIQUE Uniparental Disomy (UPD) in Clinical Genetics A Guide for Clinicians and Patients With Contributions by Unique 123 Thomas Liehr UNIQUE Institut für Humangenetik The Rare Chromosome Disorder Universitätsklinikum Jena Support Group Jena Caterham, Surrey Germany UK ISBN 978-3-642-55287-8 ISBN 978-3-642-55288-5 (eBook) DOI 10.1007/978-3-642-55288-5 Springer Heidelberg New York Dordrecht London Library of Congress Control Number: 2014937951 Ó Springer-Verlag Berlin Heidelberg 2014 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Author’s Disclaimer: The clinical details given for specific chromosomal imbalances, mutations and epigenetic changes (UPD), including such regions causing, according to present knowledge, no harm, represent the presently available data. They can be used for interpretation of molecular and cytogenetic findings—however, there are always exceptions from the findings to be expected. Some are described in this book. Thus, please use this information carefully! The author does not take any responsibility for (mis)interpretation of the data provided in this book. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Preface Uniparental disomy (UPD) is a topic, which normally is considered to be some- thing molecular genetics has to take care of exclusively. As UPD is characterized by microsatellite analyses in the majority of the cases, which is obviously a molecular genetic approach, this assumption was never really scrutinized during the last decades. I came across the topic UPD as a molecular cytogeneticist working on small supernumerary marker chromosomes (sSMC) (Liehr 2012 and 2014d). Besides centromere-near imbalances, mosaicism, and other factors, UPD also has to be considered in sSMC carriers exhibiting clinical problems. As reviews on UPD are scarce I started in 2010 collecting all published UPD cases in a freely available database (Liehr 2010 and 2014c) and went more and more into this topic. Surprisingly, at least for me, it turned out: UPD is a chromosomal disorder and thus it has to be a primary topic not only for molecular geneticists but also and especially for cytogeneticists. This is valid, as chromosomal alterations being detectable in *30 % of UPD cases, can be not only a hint on UPD presence; they also can be (and most often are) the underlying reason for UPD-formation. UPD in clinical cases most often is based on extensive, impressive, and yet not well understood capacities of human cells to correct chromosomal imbalances and/or rearrangements. UPD provides otherwise impossible insights in these repair capacities, which appear during gametogenesis and early embryogenesis. Most interesting, there is also so-called acquired UPD, which seems to be of tremendous relevance in tumor progression. As UPD leads to a group of rare diseases in human, this book has not only the goal to collect and present the yet available information on UPD; besides also patients carrying a UPD and/or families having a child with a UPD-induced syndrome report their experiences with diagnostics, counseling and living with such a syndrome. Only the inclusion of these family reports provides a most comprehensive picture of what UPD really means. Jena, June 2014 Thomas Liehr v Acknowledgments This book would not have been possible without the support of the families telling their stories. These stories were in part provided by Unique, The Rare Chromo- some Disorder Support Group, UK (http://www.rarechromo.org). Furthermore, the research of the author related to this book was supported during recent years by the Else-Kröner-Fresenius-Stiftung (2011_A42). vii Contents 1 Introduction ........................................ 1 1.1 The Problem . 2 1.1.1 Definition and History of UPD. 3 1.1.2 Nomenclature. 3 1.2 Frequency of UPD . 9 1.2.1 Prenatal Frequencies of UPD . 9 1.2.2 Newborn Frequencies of UPD . 9 1.2.3 Postnatal Frequencies of UPD . 10 1.3 UPD and Chromosomes . 10 1.3.1 Chromosomal Origins of UPD . 10 1.3.2 UPD and the Karyotype . 11 1.4 What are the Effects of UPD? . 12 2 Formation of UPD ................................... 13 2.1 Normal Karyotype and UPD . 15 2.1.1 Segmental UPD in a Normal Karyotype . 15 2.2 Aberrant Balanced Karyotype . 16 2.2.1 Translocations . 16 2.2.2 Complementary Isochromosomes . 20 2.2.3 Other Rearrangements. 22 2.2.4 Segmental UPD in a Balanced Karyotype . 23 2.3 Aberrant Unbalanced Karyotype. 23 2.3.1 Gain of Genetic Material and UPD. 24 2.3.2 Loss of Genetic Material and UPD . 33 2.4 UPD and Mosaicism . 35 2.5 Which Type of Formation Should be Considered? . 37 3 UPD in Diagnostics and Genetic Counseling ................ 39 3.1 UPD Diagnostics . 39 3.1.1 Molecular Genetics. 40 3.1.2 How to Characterize a UPD. 41 3.2 Personal Experiences of a Family Who Obtained the Diagnosis of UPD(15)pat for Their Daughter . 42 ix x Contents 3.3 UPD in Genetic Counseling . 45 3.3.1 General Remarks on UPD in Genetic Counseling. 45 3.3.2 UPD and Maternal Age Effect . 46 3.3.3 UPD and In Vitro Fertilization. 46 3.3.4 UPD-Related Disorders and Genetic Counseling . 47 4 UPD Related Syndromes Caused by Imprinting.............. 49 4.1 Paternal UPD(6) Syndrome (Transient Neonatal Diabetes). 52 4.1.1 Clinical Characteristics . 52 4.1.2 Cytogenetic Characteristics . 53 4.2 Maternal UPD(7) and Maternal UPD(11) Syndrome (Silver–Russell Syndrome). 54 4.2.1 Clinical Characteristics . 54 4.2.2 Cytogenetic Characteristics . 55 4.2.3 Personal Experiences of a Family Obtaining the Diagnosis of UPD(7)mat for Their Daughter . 55 4.3 Paternal UPD 11 and Paternal UPD 7 Syndrome (Beckwith–Wiedemann syndrome) . 57 4.3.1 Clinical Characteristics . 57 4.3.2 Cytogenetic Characteristics . 58 4.3.3 Personal Experiences of a Family Obtaining the Diagnosis of UPD(11)pat for Their Son . 58 4.4 Maternal UPD 14 Syndrome (Temple Syndrome). 60 4.4.1 Clinical Characteristics . 61 4.4.2 Cytogenetic Characteristics . 61 4.4.3 Personal Patient Reports . 61 4.5 Paternal UPD 14 Syndrome (Kagami Syndrome) . 73 4.5.1 Clinical Characteristics . 73 4.5.2 Cytogenetic Characteristics . 73 4.6 Maternal UPD 15 Syndrome (Prader–Willi Syndrome) . 74 4.6.1 Clinical Characteristics . 74 4.6.2 Cytogenetic Characteristics . 74 4.7 Paternal UPD 15 Syndrome (Angelman Syndrome) . 75 4.7.1 Clinical Characteristics . 75 4.7.2 Cytogenetic Characteristics . 75 4.7.3 Personal Patient Report . 76 4.8 Paternal UPD 20 Syndrome (Pseudohypoparathyroidism Type Ib) . 76 4.8.1 Clinical Characteristics . 76 4.8.2 Cytogenetic Characteristics . 76 Contents xi 5 Maternal UPD by Chromosome ......................... 79 5.1 Chromosome 1. 79 5.1.1 UPD(1)mat Without Clinical Consequences. 80 5.1.2 UPD(1)mat with Clinical Consequences . 80 5.2 Chromosome 2. 82 5.2.1 UPD(2)mat Without Clinical Consequences. 82 5.2.2 UPD(2)mat with Clinical Consequences . 82 5.3 Chromosome 3. 83 5.3.1 UPD(3)mat Without Clinical Consequences. 83 5.3.2 UPD(3)mat with Clinical Consequences . 84 5.4 Chromosome 4. 84 5.4.1 UPD(4)mat Without Clinical Consequences. 85 5.4.2 UPD(4)mat with Clinical Consequences . 85 5.5 Chromosome 5. 86 5.5.1 UPD(5)mat Without Clinical Consequences. 86 5.5.2 UPD(5)mat with Clinical Consequences . 86 5.6 Chromosome 6. 87 5.6.1 UPD(6)mat Without Clinical Consequences. 87 5.6.2 UPD(6)mat with Clinical Consequences . 87 5.6.3 Personal Experiences of a Family Obtaining the Diagnosis of UPD(6)mat for Their Daughter . 88 5.7 Chromosome 7. 90 5.7.1 UPD(7)mat Without Clinical Consequences. 90 5.7.2 UPD(7)mat with Clinical Consequences . 91 5.7.3 Case Report . 91 5.8 Chromosome 8. 92 5.8.1 UPD(8)mat Without Clinical Consequences. 92 5.8.2 UPD(8)mat with Clinical Consequences . 92 5.9 Chromosome 9.
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