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Utilizing Multiplex Ligation-Dependent Probe Amplification to Detect Novel Clemson University TigerPrints All Dissertations Dissertations 12-2008 Utilizing Multiplex Ligation-dependent Probe Amplification to Detect Novel X-linked Microduplications Which Cause Intellectual Disability Dianne Cohn Clemson University, [email protected] Follow this and additional works at: https://tigerprints.clemson.edu/all_dissertations Part of the Genetics Commons Recommended Citation Cohn, Dianne, "Utilizing Multiplex Ligation-dependent Probe Amplification to Detect Novel X-linked Microduplications Which Cause Intellectual Disability" (2008). All Dissertations. 299. https://tigerprints.clemson.edu/all_dissertations/299 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]. UTILIZING MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION TO DETECT NOVEL X-LINKED MICRODUPLICATIONS WHICH CAUSE INTELLECTUAL DISABILITY A Dissertation Presented to the Graduate School of Clemson University In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Genetics by Dianne Marie Cohn December 2008 Accepted by: Dr. Michael J. Friez, Committee Chair Dr. Albert Abbott Dr. Barbara Dupont Dr. Jeff Tomkins ABSTRACT A number of conditions related to X-linked intellectual disabilities (XLID) are in part due to microduplications that are not visible cytogenetically. With the focus on Rho, Ras and Rab genes, a family of genes known to be associated with intellectual disabilities, were screened for dosage aberrations (Leeuwen, F. N. 1997), (Ng, E. L. 2008), (Gissen, P. 2007), (Gurkan, C. 2005). Cohorts of intellectually disabled ID individuals were explored with new technologies. These new technologies include comparative genomic hybridization (CGH), multiplex ligation dependent probe amplification (MLPA) and quantitative PCR (qPCR) (Madrigal, I. 2007), (Hermsen, M. A. 2005), (Morey, J. S. 2006). The first screening was of two groups of individuals, one group with hypotonia and varying degrees of ID and the other of individuals with nonsyndromic ID and a suspected X-linked etiology. These cohorts were screened using the Mental Retardation on the X chromosome (MRX) kit, which focuses on genes that cause intellectual disability and are located on the X chromosome. The second screening consisted of the two former groups and 5 additional cohorts totaling 1152 patients, using a synthetic probe kit that was designed to target primarily Ras, Rab and Rho X-linked genes that were not covered by the MRX kit. The 5 additional cohorts were individuals that had normal sequencing results for one of the following X-linked genes XNP, L1CAM, UBE3A, FGD1, and STK9. The MRX screening produced a GDI1 duplication, deletion in FACL4 and an FMR2 missense mutation (c.474C>T). The synthetic MLPA screening found a partial ii XNP duplication (248kb), a 1p36 duplication/deletion complex rearrangement and a greater than 3Mb 1p36 deletion. It has been concluded from this study that duplications in these genes are rare, appearing in less than 1% in these chosen populations. Another section of this project is the characterization of a 275kb Xq25 duplication found during routine MLPA testing for MECP2. An Xq25 control peak on the MRC Holland MECP2 MLPA revealed a duplication in a female that presented with a MECP2 phenotype (Chahrour, M. 2007). This duplication spanned four genes (AIF, ELF4, BCORL1 and RAB33A) and of these four, two were over-expressed (AIF and RAB33A). Using qPCR to look for the link that may cause the similar phenotype to Rett syndrome in this patient, 26 Ras, Rab and Rho genes were tested in patients with Rett syndrome, Fragile X syndrome, ID with unknown etiology and the Xq25 patient. A similar pattern of expression was seen in this small cohort with ID. The CREB1 gene, the co-activator of MECP2, part of the transcription factor complex for 21 of the 26 genes screened, plays a role in all of these conditions and may be the linking factor in producing these patterns. The over expression of the AIF gene seemed to play a role in the mis-regulation of many genes, but with uncertainty on how it led to any affect on the phenotype. In this study duplications that play a role in the causation of ID were found using MLPA technology. As array CGH becomes more refined, with higher coverage and better software, the finding of microduplications that cause ID will increase. iii DEDICATION I would like to dedicate this endeavor to my husband, Alan, who has supported me, helped me, and given me inspiration and encouragement when tired. Listened to all my talks, usually late at night and given me advice. But most of all for his unending love. iv ACKNOWLEDGMENTS I would like to thank my committee for having faith in me, guiding me and never giving up on me. I have been blessed to have such special people in my life. Most of all I would like to thank Dr Mike Friez for his support, unending patience, guidance, and friendship throughout this endeavor. I cannot give enough thanks and words cannot express my appreciation for him being there for me. v TABLE OF CONTENTS Page TITLE PAGE....................................................................................................................i ABSTRACT.................................................................................................................…ii DEDICATION................................................................................................................iv ACKNOWLEDGMENTS ...............................................................................................v LIST OF TABLES..........................................................................................................ix LIST OF FIGURES ........................................................................................................x LIST OF ABBREVIATIONS ......................................................................................xiii I. INTRODUCTION ........................................................................................1 II. BACKGROUND ...........................................................................................6 III. COLLABORATION....................................................................................16 IV. RESEARCH DESIGN AND METHODS...................................................17 Importance of study .....................................................................................17 Purpose of study...........................................................................................21 Explanation of research................................................................................22 MLPA ..........................................................................................................25 Overview of methodology decisions ...........................................................30 V. RESULTS: MRX MLPA.............................................................................37 GDI1 and PQBP1 Duplication.....................................................................39 FACL4 Deletion...........................................................................................42 FMR2 Point Mutation..................................................................................46 FMR2 Background.......................................................................................51 vi VI. RESULTS:XNP DUPLICATION CAUSES ATRX ...................................52 Case Report..................................................................................................53 XNP Results .................................................................................................56 ATRX Background ......................................................................................61 VII. RESULTS: L1CAM AND SKI DUPLICATIONS.......................................63 L1CAM/NEMO ............................................................................................63 1p36 Background.........................................................................................64 1p36 Case 56560..........................................................................................66 1p36 Results 56560......................................................................................67 1p36 Case 60175..........................................................................................71 1p36 Results 60175......................................................................................72 VIII. RESULTS: Xq25 DUPLICATION .............................................................74 Xq25 Duplication.........................................................................................74 Xq25 Case background................................................................................77 Xq25 Proband Physical Examination and Report........................................77 Xq25 Data Results .......................................................................................78 RAB33A Global Expression Changes ..........................................................84 Expression Screening...................................................................................99 IX. RESULTS: RT2 PROFILER SUPER ARRAY..........................................103 X. DISCUSSION............................................................................................111 FACL4 Deletion.........................................................................................113
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