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Analysis of Genotype, Phenotype, and Age Progression in Phelan-Mcdermid Syndrome Sara Sarasua Clemson University, [email protected]

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Analysis of Genotype, Phenotype, and Age Progression in Phelan-Mcdermid Syndrome Sara Sarasua Clemson University, Sarasua@Mindspring.Com Clemson University TigerPrints All Dissertations Dissertations 12-2012 Analysis of Genotype, Phenotype, and Age Progression in Phelan-McDermid Syndrome Sara Sarasua Clemson University, [email protected] Follow this and additional works at: https://tigerprints.clemson.edu/all_dissertations Part of the Genetics and Genomics Commons Recommended Citation Sarasua, Sara, "Analysis of Genotype, Phenotype, and Age Progression in Phelan-McDermid Syndrome" (2012). All Dissertations. 1032. https://tigerprints.clemson.edu/all_dissertations/1032 This Dissertation is brought to you for free and open access by the Dissertations at TigerPrints. It has been accepted for inclusion in All Dissertations by an authorized administrator of TigerPrints. For more information, please contact [email protected]. ANALYSIS OF GENOTYPE, PHENOTYPE, AND AGE PROGRESSION OF PHELAN-MCDERMID SYNDROME A Dissertation Presented to the Graduate School of Clemson University In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Genetics by Sara Moir Sarasua December 2012 Accepted by: Dr. Amy Lawton-Rauh, Committee Chair Dr. Chin-Fu Chen Dr. Leigh Anne Clark Dr. Barbara R. DuPont Dr. Alex Feltus ABSTRACT Phelan-McDermid syndrome is a developmental disability syndrome associated with deletions of the terminal end of one copy of chromosome 22q13. The observed chromosomal aberrations include simple terminal deletions, interstitial deletions, deletions and duplications, and duplications without deletions. All patients have some degree of developmental disability and many also have hypotonia, autism, minor dysmorphic features, and seizures. I performed an epidemiological and cytogenetic investigation to better understand the etiology of Phelan- McDermid syndrome and to provide information to patients and their families, clinicians, and researchers investigating developmental disabilities. Deletions vary widely in size, from 60 kb to more than 9 Mb, but almost all cases are missing one copy of the subtelomeric gene SHANK3, a candidate gene for neurological features. The results of this study established that larger deletions are associated with more severe disability establishing the rationale to investigate the role of additional genes or genomic regions for clinical features. Statistical association analyses identified specific genomic regions as associated with 22 clinical features. In particular, speech is highly correlated with deletion size indicating that speech-related genes or genomic elements located in genomic bands 22q13.2q13.31 may be critical in determining a patient’s ability to communicate verbally. The use of protein interaction networks identified candidate genes within these narrowed genomic regions. Also, a longitudinal assessment of phenotypes observed among individuals aged 0.4 to 64 years established significant variation of phenotypes by age, such that future investigations need to take age into account when conducting genotype-phenotype studies. In particular, we find that behavioral difficulties subside and low ii muscle tone becomes less prominent as children age, however seizures, autism, and some chronic diseases become more apparent in teens and adults. iii DEDICATION I dedicate this work to my family for their unwavering support. iv ACKNOWLEDGMENTS This work would not be possible without the dedicated efforts of the patients and families of patients with Phelan-McDermid syndrome. I specifically acknowledge the support and guidance from Drs. Katy Phelan, Barbara DuPont, Luigi Boccuto, Curtis Rogers, Charles Schwartz, and Roger Stevenson. I thank my committee members Drs. Amy Lawton-Rauh, Chin-Fu Chen, Leigh Anne Clark, Barbara DuPont, and Alex Feltus for their helpful suggestions throughout my training. Finally, I thank my late advisor, Dr. Julianne Collins, who set the standard to learn as much as possible about developmental disabilities and birth defects to help patients as much as possible. v TABLE OF CONTENTS Page TITLE PAGE ..................................................................................................................................... i ABSTRACT ..................................................................................................................................... ii DEDICATION ................................................................................................................................ iv ACKNOWLEDGMENTS .................................................................................................................. v LIST OF TABLES ............................................................................................................................ ix LIST OF FIGURES .......................................................................................................................... xi PREFACE........................................................................................................................................ 1 CHAPTER I. CHROMOSOMAL ANOMALIES AND CLINICAL FEATURES ASSOCIATED WITH CHROMOSOME 22Q13 ............................................................... 5 Overview ............................................................................................... 6 Chromosome 22 and Chromosomal Rearrangements .......................... 7 History of 22q13 Deletion Syndrome .................................................. 12 PMS Clinical Features .......................................................................... 20 Comparison with Other Deletion Syndromes ..................................... 26 Challenges in Defining Phenotypes in Human Deletion Syndrome Studies .................................................................................... 28 Biological Basis of the Neurological Phenotypes of PMS and Identification of SHANK3 as a Candidate Gene ...................... 30 Beyond PMS, What is Known about Phenotypes Associated With 22q13? ........................................................................... 41 Summary ............................................................................................. 45 References ........................................................................................... 57 vi Table of Contents (Continued) Page II. ASSOCIATION BETWEEN DELETION SIZE AND IMPORTANT PHENOTYPES EXPANDS THE REGION OF INTEREST IN PHELAN-MCDERMID SYNDROME (22Q13 DELETION SYNDROMES) ..................................... 78 Abstract ............................................................................................... 79 Introduction......................................................................................... 80 Subjects and Methods ......................................................................... 82 Results ................................................................................................. 85 Discussion ............................................................................................ 88 Summary ............................................................................................. 93 References ......................................................................................... 102 III. 22Q13.2Q13.32 GENOMIC REGIONS ASSOCIATED WITH SEVERITY OF SPEECH DELAY, DEVELOPMENTAL DELAY, AND PHYSICAL FEATURES IN PHELAN-MCDERMID SYNDROME............................. 107 Abstract .......................................................................................... 108 Introduction ................................................................................... 109 Materials and Methods .................................................................. 110 Results ............................................................................................ 114 Discussion ....................................................................................... 119 Conclusion ...................................................................................... 128 References ..................................................................................... 147 IV. CLINICAL AND GENOMIC FEATURES OF PHELAN-MCDERMID SYNDROME IN A LONGITUDINAL ASSESSMENT OF 201 PATIENTS .................... 155 Abstract .......................................................................................... 156 Introduction ................................................................................... 157 Methods ......................................................................................... 159 Results ............................................................................................ 164 Discussion ....................................................................................... 170 Conclusion ...................................................................................... 177 References ..................................................................................... 195 vii Table of Contents (Continued) Page V. CONCLUSIONS ........................................................................................................ 200 APPENDICES ................................................................................................................. 203 A. EFFECT OF POPULATION STRATIFICATION ON THE IDENTIFICATION OF SIGNIFICANT SINGLE NUCLEOTIDE POLYMORPHISMS IN GENOME-WIDE ASSOCIATION STUDIES ............................................ 204 B. LIST OF ABBREVIATIONS ............................................................................ 216 viii LIST OF TABLES Table Page 1.1 Common Features of
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