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Investigation of the Genetic Cause of Hearing Loss In INVESTIGATION OF THE GENETIC CAUSE OF HEARING LOSS IN NEWFOUNDLAND FAMILIES by © Cindy Penney Thesis submitted to the School of Graduate Studies in partial fulfillment of the requirements for the degree of Master of Science Medicine Human Genetics/Faculty of Medicine Memorial University of Newfoundland May 2018 St. John’s Newfoundland and Labrador Abstract The purpose of this study was to determine the genetic cause of hearing loss in a seven-generation Newfoundland family. Twenty-nine family members were recruited segregating autosomal dominant hearing loss. Genome-wide SNP genotyping and linkage analysis showed significant linkage (LOD=4.77) to chromosome 13q34. The region contained 26 genes and a known deafness locus (DFNA33). Exome sequencing identified 13 variants of interest within the linked region, but only 3 co-segregated with hearing loss: F10 c.865+26C>T, ADPRHL1 c.380-17C>A and c.380-16T>G. All three were absent from 81 population controls, yet the ADPRHL1 c.380-17C>A and c.380-16T>G were identified in two other probands with hearing loss. All three were predicted to affect splicing of nearby exons, however cDNA analysis of ADPRHL1 showed no effect. F10 c.865+26C>T, ADPRHL1 c.380-17C>A and c.380-16T>G are rare, co- segregate with hearing loss, and are possibly pathogenic. Conversely, they may help form a disease haplotype and exist in linkage disequilibrium with the causal mutation. However, the putative ADPRHL1 variants have been found in multiple families with hearing loss and further investigations are necessary to elucidate their effect. ii Acknowledgements My thesis project has been an exciting learning experience. It gave me the opportunity to learn the latest molecular genetics techniques, to be involved in clinical recruitment and testing and to meet the families our research impacts. Over the course of my Master’s I have received an enormous amount of support and there are many people I would like to thank. First, I would like to thank my supervisor, Dr. Terry-Lynn Young, and my supervisory committee of Dr. Darren O’Rielly and Dr. Susan Stanton, for their guidance throughout my Master’s program. I would like to thank past and current members of the Young Lab who have taught me a wide range of laboratory techniques, especially Mrs. Tammy Benteau, Mr. Justin Pater, Mr. Dante Galutira, and Dr. Nelly Abdelfatah. I would also like to thank Mr. Jim Houston for his help in troubleshooting difficult techniques as I could always rely on his experience to guide me in the right direction. I am grateful to Ms. Sarah Predham and Dr. Kathy Hodgkinson for their work in ascertaining more family members on our trip to Deer Lake. I would like to thank Ms. Anne Griffin, for her help in recruitment, audiological testing, and phenotyping. I would like to thank members of the Rahman-O’Rielly Lab which were always ready to offer technical expertise, especially during the development of the next- generation sequencing (NGS) protocol. I would like to thank the participants and their families, without which my research would not be possible. I would also like to thank the Research & Development iii Corporation (RDC) of Newfoundland and Labrador, the Canadian Institutes of Health Research (CIHR), and Memorial University of Newfoundland and Labrador (MUN) for their financial support. I would like to give a special thanks to the Janeway Children's Health and Rehabilitation Centre, for use of their audiology testing space. Thanks to Nicole Roslin and the Center for Applied Genomics in Toronto for completing the genome-wide SNP genotyping and linkage analysis. I would also like to thank the reviewers for their constructive criticisms and insightful comments that have led to an improved thesis. I would especially like to thank David Metcalfe, my husband, for his support during my Master’s program and his assistance in editing my thesis. Lastly, I would like to thank my parents for their unending support and encouragement throughout my academic career. iv Table of Contents Abstract ............................................................................................................................... ii Acknowledgements ............................................................................................................ iii Table of Contents ................................................................................................................. v List of Tables ...................................................................................................................... vi List of Figures ................................................................................................................... vii List of Abbreviations and Symbols .................................................................................. viii List of Appendices ............................................................................................................ xii Chapter 1 Introduction ......................................................................................................... 1 Genetic Variation and the Human Genome ..................................................................... 1 Auditory Function and Hearing Loss ............................................................................... 8 The Newfoundland Population and Genetic Research .................................................. 22 Chapter 2 Materials and Methods ...................................................................................... 34 Patient Recruitment ........................................................................................................ 34 Experimental Design ...................................................................................................... 39 Genome-Wide SNP Genotyping and Linkage Analysis of Family 2070 ...................... 40 Next-Generation Sequencing of Family 2070 ............................................................... 41 Sanger Sequencing ......................................................................................................... 44 cDNA Analysis of Family 2070 .................................................................................... 49 Chapter 3 Results ............................................................................................................... 52 Hearing Loss in Family 2070 ......................................................................................... 52 Hearing Loss in Additional Families ............................................................................. 56 Results of Genome-Wide SNP Genotyping and Linkage Analysis of Family 2070 ..... 62 Results of Next-Generation Sequencing of Family 2070 .............................................. 64 Results of Sanger Sequencing ........................................................................................ 67 Results of cDNA Analysis of Family 2070 ................................................................... 73 Chapter 4 Discussion ......................................................................................................... 76 Chapter 5 Summary ........................................................................................................... 90 Bibliography ...................................................................................................................... 92 Appendix .......................................................................................................................... 104 v List of Tables Table 1.1 Reported Newfoundland Deafness Mutations to Date November 11th, 2017 .... 32 Table 3.1 Phenotype of Inherited Hearing Loss in Family 2070 ....................................... 54 Table 3.2 Phenotype of Hearing Loss in Families 2110 and 2143 .................................... 59 Table 3.3 Thirteen Variants which Passed Filtering of Exome Variant Datasets .............. 66 vi List of Figures Figure 1.1 Mechanism of Alternative Splicing .................................................................... 7 Figure 1.2 Basic Structure of the Human External, Middle and Inner ear. ....................... 10 Figure 1.3 Detailed Structure of the Human Inner Ear ...................................................... 10 Figure 1.4 Structure of a Human Hair Cell of the Inner Ear .............................................. 11 Figure 1.5 Audiogram Depicting the Characterization of Hearing Loss Severity ............. 14 Figure 1.6 Audiograms Depicting Normal Hearing and Examples of Hearing Loss. ....... 18 Figure 1.7 Flowchart Outlining the Newfoundland Hereditary Hearing Loss Study ........ 33 Figure 2.1 Pedigree of Family 2070................................................................................... 36 Figure 2.2 Pedigree of Family 2070 with Recruitment Data ............................................. 37 Figure 2.3 Family 2070 Recruitment Timeline .................................................................. 38 Figure 3.1 Audiograms from Family 2070 ........................................................................ 55 Figure 3.2 Audiograms from Families 2110 and 2143 ...................................................... 60 Figure 3.3 Pedigrees of Families 2110 and 2143 ............................................................... 61 Figure 3.4 Electropherograms of Heterozygous F10 c.865+26C>T Variant .................... 68 Figure 3.5 Electropherograms of Heterozygous ADPRHL1 c.380-17C>A and c.380- 16T>G Variants ........................................................................................................
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