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UITNODIGING GENETIC DIAGNOSIS Voor het bijwonen van de openbare verdediging van AND RESPIRATORY het proefschrift Genetic diagnosis and respiratory management of primary ciliary dyskinesia dyskinesia ciliary of primary management respiratory and diagnosis Genetic GENETIC DIAGNOSIS MANAGEMENT OF AND RESPIRATORY MANAGEMENT OF PRIMARY CILIARY PRIMARY CILIARY DYSKINESIA DYSKINESIA Door Tamara Paff Tamara Paff dinsdag 7 november 2017 11:45 uur in de aula van de Vrije Universiteit de Boelelaan, 1105 TE Amsterdam Receptie aansluitend in Grand cafe The Basket op de VU campus Tamara Paff Johann Keplerstraat 8-1 hoog 1098 HL, Amsterdam +31645364292/ [email protected] Tamara Paff Tamara | Paranimfen Marian van der Meij [email protected] 06-15500488 Marc van der Schee [email protected] 06-40883602 14759 - Paff_R11,5_OMS_DEF.indd 1 25-09-17 10:25 UITNODIGING GENETIC DIAGNOSIS Voor het bijwonen van de openbare verdediging van AND RESPIRATORY het proefschrift Genetic diagnosis and respiratory management of primary ciliary dyskinesia dyskinesia ciliary of primary management respiratory and diagnosis Genetic GENETIC DIAGNOSIS MANAGEMENT OF AND RESPIRATORY MANAGEMENT OF PRIMARY CILIARY PRIMARY CILIARY DYSKINESIA DYSKINESIA Door Tamara Paff Tamara Paff Dag datum tijdstip in de aula van de Vrije Universiteit de Boelelaan, 1105 TE Amsterdam Receptie aansluitend in Grand cafe The Basket op de VU campus Tamara Paff Johann Keplerstraat 8-1 hoog 1098 HL, Amsterdam +31645364292/ [email protected] Tamara Paff Tamara Paranimfen Marian van der Meij | [email protected] 06-15500488 Marc van der Schee [email protected] 06-40883602 14759_TPaff_BW.indd 1 19-09-17 13:08 ProefschriftTamaraPaff_Cover+Bladwijzer.indd All Pages 15-08-17 12:47 The studies performed in this thesis were financially supported by the PCD support group (PCD belangengroep), Fonds NutsOhra, the “Dutch mudder” team and Chiesi. Financial support for publication of this thesis was generously provided by Stichting Researchfonds Kindergeneeskunde VUmc. Cover: studioLIN - www.studiolin.nl Lay-out: Nikki Vermeulen - Ridderprint BV Printing: Ridderprint BV - www.ridderprint.nl ISBN: 978-94-6299-747-9 Copyright 2017 by T. Paff. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means without prior permission of the holder of the copyright. Dedicated to the Dutch PCD support group Opgedragen aan de Nederlandse PCD Belangengroep 14759_TPaff_BW.indd 2 19-09-17 13:08 VRIJE UNIVERSITEIT Genetic Diagnosis and Respiratory Management of Primary Ciliary Dyskinesia ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. V. Subramaniam, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de faculteit der Geneeskunde op dinsdag 7 november 2017 om 11.45 uur in de aula van de universiteit, De Boelelaan 1105 door Tamara Paff geboren te Lisse 14759_TPaff_BW.indd 3 19-09-17 13:08 promotor: prof.dr. A. Vonk Noordegraaf copromotoren: dr. E.G. Haarman dr. G. Pals dr. J.M.A. Daniels 14759_TPaff_BW.indd 4 19-09-17 13:08 TABLE OF CONTENTS Chapter 1 General introduction 7 Adapted from: Primary ciliary dyskinesia: From diagnosis to molecular mechanisms Journal of Pediatric Genetics (2014); 3(2)115-127 Diagnostic methods in Primary Ciliary Dyskinesia Paediatric Respiratory Reviews (2016); 18: 8-17 PART I GENETIC DIAGNOSIS Chapter 2 Splice-site mutations in the axonemal outer dynein arm docking 35 complex gene CCDC114 cause primary ciliary dyskinesia American Journal of Human Genetics (2013); 92(1): 88-98 Chapter 3 Mutations in PIH1D3 cause X-linked primary ciliary dyskinesia with 55 outer and inner dynein arm defects American Journal of Human Genetics (2017); 100(1):160-168 Chapter 4 Diagnostic yield of a targeted gene panel in Dutch primary ciliary 75 dyskinesia patients Peer review by Human Mutation PART II RESPIRATORY MANAGEMENT Chapter 5 Breathomics in lung disease 101 Chest (2015); 147(1): 224-231 Chapter 6 Exhaled molecular profiles in the assessment of cystic fibrosis and 117 primary ciliary dyskinesia Journal of Cystic Fibrosis (2013); 12(5): 454-460 Chapter 7 A randomised controlled trial on the effect of inhaled hypertonic 131 saline on quality of life in primary ciliary dyskinesia European Respiratory Journal (2017); 49(2). pii: 1601770 Chapter 8 General discussion 149 Not published Supplementary files 173 English summary 205 Nederlandse samenvatting 211 List of publications 217 Dankwoord 221 Curriculum vitae 231 14759_TPaff_BW.indd 5 19-09-17 13:08 14759_TPaff_BW.indd 6 19-09-17 13:08 1 GENERAL INTRODUCTION Adapted from: Tamara Paff; Johannes M.A. Daniels; Gerard Pals; Eric G. Haarman. Primary ciliary dyskinesia: From diagnosis to molecular mechanisms Journal of Pediatric Genetics (2014); 3(2)115-127 Jane S. Lucas; Tamara Paff; Patricia Goggin; Eric G. Haarman. Diagnostic methods in Primary Ciliary Dyskinesia Paediatric Respiratory Reviews (2016); 18: 8-17 14759_TPaff_BW.indd 7 19-09-17 13:08 14759_TPaff_BW.indd 8 19-09-17 13:08 9 Motile cilia line the entire respiratory tract and are responsible for “sweeping” the airways, thereby removing inhaled noxious substances and micro-organisms. By doing so these hair- like organelles are an important component of the body’s innate immune system. Patients with an inherited defect in this ciliary motility consequently suffer from frequent upper and lower respiratory tract infections, eventually leading to permanent lung damage (i.e. bronchiectasis). Diagnosing primary ciliary dyskinesia (PCD) at an early stage is thought to improve pulmonary outcome later in life [1, 2]. As there is no single gold standard test, several tests that require expert skills to perform and to interpret need to be combined. In recent years, the wide-spread use of next-generation sequencing (NGS), allowing high- throughput sequencing of DNA, accelerated the discovery of PCD-related genes. These advances opened up the possibility of genetic testing in the diagnostic approach, requiring the establishment of its exact role. The respiratory management of PCD patients is hampered by the lack of scientific evidence. As patients with cystic fibrosis (CF) suffer from similar pulmonary infections, management of PCD is primarily based on extrapolations from CF guidelines and personal experiences. This approach is understandable but questionable, as CF and PCD have distinct underlying pathophysiology. The aims of this thesis are (1) to gain more insight into the genetic background of Dutch PCD patients and the role of genetic testing in the diagnostic approach and (2) to gain more insight in the respiratory management of PCD. In chapter 1 I aim to provide a complete overview of PCD characteristics, diagnostic methods and options for respiratory management to put the other chapters of this thesis into perspective. HISTORY OF PRIMARY CILIARY DYSKINESIA In 1904, Siewart (or Zivat, Zivert, Sivert) described a 21 year old with bronchiectasis associated with situs inversus (i.e. a complete mirror image of the internal organs) [3]. Kartagener later reported the triad of bronchiectasis, situs inversus and sinusitis in 1933, but it was not until the mid-1970s that Afzelius and Pedersen recognized infertility as a feature and proposed the unifying role of cilia to explain the syndrome [4–6]. Having noted absent dynein arms in the cilia of patients with the syndrome, Afzelius later demonstrated that the cilia were immotile, prompting the change of name from 'Kartagener’s Syndrome' to 'Immotile Cilia Syndrome' [5]. These reports provided the evidence for assessment of the ciliary ultrastructure and motility as the basis of diagnostic testing. Recognition that outer dynein arm anomalies were not the only ultrastructural defect associated with the syndrome gave early insights into the underlying heterogeneity of the disorder [7, 8]. Following recognition that a number of Introduction patients had motile but dyskinetic cilia the name was further changed in the mid-1980s to . 'primary ciliary dyskinesia' [9–12]. CHAPTER 1 CHAPTER 14759_TPaff_BW.indd 9 19-09-17 13:08 10 CHAPTER 1 CLINICAL CHARACTERISTICS PCD is a rare disease occurring in an estimated 1:10.000 – 1:30.000 newborns. It is important for clinicians to recognize phenotypic features of PCD to enable diagnosis at an early age [13, 14]. This can be a major challenge as some disease characteristics show overlap with more frequently occurring respiratory diseases in childhood, such as recurrent airway infections without an underlying disease, asthma, immune deficiencies, congenital malformations of the lungs and airways (like bronchomalacia) or even (mild) CF. In table 1 clinical features are summarized that should raise the suspicion of PCD and prompt referral to a specialized diagnostic center [15]. Symptoms can be classified by the organ systems in which cilia are present; the respiratory system, the embryonic node and the reproductive system. Table 1. Who to refer for diagnostic testing. Patients with early onset of recurrent respiratory tract symptoms and any of the following: 1. Situs inversus (SI) totalis or any heterotaxic syndrome (approximately 50% have normal situs) 2. Neonatal nasal congestion and/ or unexplained neonatal distress in term infants 3. Positive family history for PCD 4. Males with dysmotile sperm 5. Persistent productive cough/ bronchiectasis / severe upper airway after more common causes like allergies, asthma, immune deficiencies
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    Looking for Missing Proteins in the Proteome of Human Spermatozoa: An Update Yves Vandenbrouck, Lydie Lane, Christine Carapito, Paula Duek, Karine Rondel, Christophe Bruley, Charlotte Macron, Anne Gonzalez de Peredo, Yohann Coute, Karima Chaoui, et al. To cite this version: Yves Vandenbrouck, Lydie Lane, Christine Carapito, Paula Duek, Karine Rondel, et al.. Looking for Missing Proteins in the Proteome of Human Spermatozoa: An Update. Journal of Proteome Research, American Chemical Society, 2016, 15 (11), pp.3998-4019. 10.1021/acs.jproteome.6b00400. hal-02191502 HAL Id: hal-02191502 https://hal.archives-ouvertes.fr/hal-02191502 Submitted on 19 Mar 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Journal of Proteome Research 1 2 3 Looking for missing proteins in the proteome of human spermatozoa: an 4 update 5 6 Yves Vandenbrouck1,2,3,#,§, Lydie Lane4,5,#, Christine Carapito6, Paula Duek5, Karine Rondel7, 7 Christophe Bruley1,2,3, Charlotte Macron6, Anne Gonzalez de Peredo8, Yohann Couté1,2,3, 8 Karima Chaoui8, Emmanuelle Com7, Alain Gateau5, AnneMarie Hesse1,2,3, Marlene 9 Marcellin8, Loren Méar7, Emmanuelle MoutonBarbosa8, Thibault Robin9, Odile Burlet- 10 Schiltz8, Sarah Cianferani6, Myriam Ferro1,2,3, Thomas Fréour10,11, Cecilia Lindskog12,Jérôme 11 1,2,3 7,§ 12 Garin , Charles Pineau .
  • Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways

    Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways

    biomolecules Article Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways Aayushi Srivastava 1,2,3,4 , Abhishek Kumar 1,5,6 , Sara Giangiobbe 1, Elena Bonora 7, Kari Hemminki 1, Asta Försti 1,2,3 and Obul Reddy Bandapalli 1,2,3,* 1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany; [email protected] (A.S.); [email protected] (A.K.); [email protected] (S.G.); [email protected] (K.H.); [email protected] (A.F.) 2 Hopp Children’s Cancer Center (KiTZ), D-69120 Heidelberg, Germany 3 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), D-69120 Heidelberg, Germany 4 Medical Faculty, Heidelberg University, D-69120 Heidelberg, Germany 5 Institute of Bioinformatics, International Technology Park, Bangalore 560066, India 6 Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India 7 S.Orsola-Malphigi Hospital, Unit of Medical Genetics, 40138 Bologna, Italy; [email protected] * Correspondence: [email protected]; Tel.: +49-6221-42-1709 Received: 29 August 2019; Accepted: 10 October 2019; Published: 13 October 2019 Abstract: Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family.