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Dissertationes Medicinae Universitatis Tartuensis 178 DISSERTATIONES MEDICINAE UNIVERSITATIS TARTUENSIS 178 DISSERTATIONES MEDICINAE UNIVERSITATIS TARTUENSIS 178 RITA TEEK The genetic causes of early onset hearing loss in Estonian children Department of Paediatrics, University of Tartu, Tartu, Estonia Dissertation is accepted for commencement of the degree of Doctor of Medical Sciences on September 22, 2010 by the Council of the Faculty of Medicine, University of Tartu, Estonia. Supervisors: Professor Katrin Õunap, MD, PhD, Department of Paediatrics, University of Tartu, Tartu, Estonia The Late Professor Mart Kull, MD, PhD, Department of Oto-Rhino-Laryngology, University of Tartu, Tartu, Estonia (2005–2008) Reviewers: Assistant Professor Gunnar Tasa, MD, PhD, Department of General and Molecular Pathology, University of Tartu, Tartu, Estonia Assistant Professor Oivi Uibo, MD, PhD, Department of Paediatrics, University of Tartu, Tartu, Estonia Opponent: Professor Lisbeth Tranebjærg, MD, PhD, Department of Audiology, H:S Bispebjerg Hospital, and Wilhelm Johannsen Centre of Functional Genomics Institute of Cellular and Molecular Medicine, ICMM, University of Copenhagen, The Panum Institute, Denmark Commencement: November 24, 2010 ISSN 1024–395x ISBN 978–9949–19–478–0 (trükis) ISBN 978–9949–19–479–7 (PDF) Autoriõigus: Rita Teek, 2010 Tartu Ülikooli Kirjastus www.tyk.ee Tellimuse nr. 570 To my patients and their families CONTENTS LIST OF ORIGINAL PUBLICATIONS ...................................................... 9 ABBREVIATIONS OF HEARING LOSS STUDY GROUPS AND PATIENTS ..................................................................................................... 10 ABBREVIATIONS ........................................................................................ 11 1. INTRODUCTION ..................................................................................... 13 2. LITERATURE REVIEW .......................................................................... 15 2.1. The epidemiology and frequency of HL ............................................ 15 2.2. Classification of hearing loss ............................................................. 17 2.3. Hereditary impaired hearing ............................................................... 18 2.3.1. Nonsyndromic hearing impairment ......................................... 18 2.3.1.1. GJB2 gene .................................................................. 18 2.3.1.1.1. c.35delG mutation ...................................... 19 2.3.1.1.2. p.M34T mutation ........................................ 22 2.3.1.1.3. Other mutations in GJB2 gene ................... 23 2.3.1.1.4. Genotype-phenotype correlations in GJB2 mutations .................................................... 24 2.3.1.2. GJB6 gene .................................................................. 25 2.3.1.3. SLC26A5 (prestin) gene.............................................. 26 2.3.1.4. SLC26A4 (pendred) gene............................................ 26 2.3.1.5. Mitochondrial mutations ............................................ 27 2.3.1.6. Other genes ................................................................. 28 2.3.2. Syndromic hearing impairment ............................................... 30 2.3.2.1. Waardenburg syndrome (WS) .................................... 31 2.3.2.2. Branchio-oto-renal (BOR) syndrome ......................... 31 2.3.2.3. Stickler syndrome ....................................................... 32 2.3.2.4. LEOPARD syndrome (LS) ........................................ 32 2.3.2.5. Usher syndrome (US) ................................................. 33 2.3.2.6. Pendred syndrome (PDS) ........................................... 34 2.3.2.7. Jervell and Lange-Nielsen syndrome ......................... 34 2.3.2.8. Alport syndrome (AS) ................................................ 35 2.4. The identification of new rare loci of HL ........................................... 35 2.5. Acquired HL ....................................................................................... 36 2.6. Newborn hearing screening ................................................................ 37 2.7. Genetic counseling of patient with HL ............................................... 37 3. AIMS OF THE PRESENT STUDY ......................................................... 40 4. MATERIAL AND METHODS ................................................................ 41 4.1. Study subjects ..................................................................................... 41 4.1.1. Study group of newborn children ............................................ 41 4.1.2. Study group of children with HL ............................................. 41 7 4.1.3. Patients with syndromic HL .................................................... 42 4.2. Methods .............................................................................................. 42 4.2.1. APEX assay for SNHL ............................................................ 42 4.2.2. PCR analysis for c.35delG and p.M34T mutations in GJB2 gene ......................................................................................... 43 4.2.3. Cytogenetic investigation ........................................................ 44 4.2.4. Illumina analysis ...................................................................... 44 4.2.5. Real time PCR analysis ........................................................... 44 4.2.6. CMV PCR analysis .................................................................. 45 4.2.7. Statistical analysis ................................................................... 45 4.2.8. Ethical considerations .............................................................. 45 5. RESULTS AND DISCUSSION ................................................................ 46 5.1. GJB2 gene .......................................................................................... 46 5.1.1. Study group of newborn children (Publication I) .................... 46 5.1.2. Study group of children with early onset HL (Publication I) . 48 5.1.3. The genotype and phenotype correlation in patients with GJB2 gene mutations (Publications I and V) .......................... 52 5.2. GJB3 and GJB6 gene (Publications I and V) .................................... 55 5.3. Two mitochondrial genes (12S rRNA and tRNA-Ser) (Publication V) 56 5.4. SLC26A5 (prestin) gene (Publication II) ............................................ 57 5.5. SLC26A4 (pendred) gene (Publication V) ......................................... 62 5.6. Syndromic HL (Publication V) .......................................................... 63 5.6.1. LEOPARD syndrome – case report (Publication IV) .............. 64 5.7. Chrosomal rearrangements ................................................................. 65 5.7.1. Results of regular karyotyping (Publication V) ............. 65 5.7.2. Results of genome array analysis ............................................ 66 5.7.2.1. Case 1 ......................................................................... 67 5.7.2.2. Case 2 ......................................................................... 70 5.7.2.3. Case 3 ......................................................................... 72 5.7.2.4. Case 4 (Publication III) .............................................. 73 5.8. Cytomegalovirus PCR analysis (Publication V) ................................ 73 6. CONCLUSIONS ....................................................................................... 75 7. REFERENCES .......................................................................................... 77 SUMMARY IN ESTONIAN ......................................................................... 94 ACKNOWLEDGEMENTS ........................................................................... 100 PUBLICATIONS ........................................................................................... 101 CURRICULUM VITAE ................................................................................ 147 ELULOOKIRJELDUS .................................................................................. 149 8 LIST OF ORIGINAL PUBLICATIONS This thesis is based on the following original publications referred to in the text by Roman numerals (I–V), and previously unpublished data: I. Teek R, Kruustük K, Zordania R, Joost K, Reimand T, Möls T, Oitmaa E, Kahre T, Tõnisson N, Õunap K. Prevalence of c.35delG and p.M34T mutations in the GJB2 gene in Estonia. Int J Pediatr Otorhinolaryngol 2010, 74(9); 1007–12. II. Teek R, Oitmaa E, Kruustük K, Zordania R, Joost K, Raukas E, Tõnisson N, Gardner P, Schrijver I, Kull M, Õunap K. Splice variant IVS2–2A>G in the SLC26A5 (Prestin) gene in five Estonian families with hearing loss. Int J Pediatr Otorhinolaryngol 2009; 73(1):103–7. III. Puusepp H, Zilina O, Teek R, Männik K, Parkel S, Kruustük K, Kuuse K, Kurg K, Õunap K. 59 Mb microdeletion in chromosome band 17q22–q23.2 associated with tracheo-esophageal fistula and conductive hearing loss. Eur J Med Genet 2009; 52(1):71–4. IV. Kalev I, Muru K, Teek R, Zordania R, Reimand T, Köbas K, Õunap K. LEOPARD syndrome with recurrent PTPN11 mutation Y279C and diffe- rent cutaneous manifestations: two case reports and a review of the literature. Eur J Pediatr 2010; 169(4):469–73. V. Teek R, Kruustük K, Zordania R, Joost K, Reimand T, Oitmaa E, Nelis M, Žilina O, Kahre T, Tõnisson N, Õunap K. Kuulmislanguse geneetilised põhjused Eesti lastel ning nendel leitud genotüübi ja fenotüübi oma- vaheline võrdlus. Eesti Arst 2010,
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