iv
TABLE OF CONTENTS
TITLE i
APPROVAL SHEET ii
REVISION APPROVAL FORM
iii
TABLE OF CONTENTS
iv
DECLARATION ACKNOWLEDGEMENT
LIST OF FIGURES, TABLES AND APPENDIX vi
vii x
ABBREVIATIONS CURRICULUM VITAE
ABSTRACT xii
xiv xv
CHAPTER I INTRODUCTION
1 I.1 Backgrounds
1 I.2 Research questions
3 I.2.1 General research questions
3 I.2.2 Specific research questions
3 I.3 Research purpose
3 I.4 Research advantages
4 I.5 Research originality
4
CHAPTER II LITERATURE REVIEW 7
II.1 Mental Retardation 7
II.1.1. Definition 7
II.1.2. Classification 7
II.1.3 Prevalence 8
II.1.4. Etiology 8
II.2. X-linked Mental Retardation 11
II.2.1. Definition 11
II.2.2. Prevalence 12
II.2.3. Classification of XLMR 12
II.2.4. Identification of genetic defects involved in XLMR 13
II.2.4.1. Positional Cloning 13
II.2.4.2. Positional Candidate Gene Analysis 17
II.2.4.3. Mutation analysis of known gene 19
II.2.4.4. Array technology 20
II.2.4.5. Next generation sequencing 20
II.3. X-Chromosome Linkage Analysis II.4. X-Chromosome Inactivation
II.5. Genetic Counselling 21
22 24
II.6. Theoritical Framework 25
CHAPTER III RESEARCH METHOD 26
III.1. Research Aspect
26
v
III.1.1. Research Field 26
III.1.2. Research Location 26
III.1.3. Research Period 26
III.1.4. Research Design 26
III.1.5. Variables 26
III.1.6. Operational Definition 27
III.1.7. Research Protocol 28
III.2. Method 29
III.2.1.Population 29
III.2.2. Samples 29
III.2.2.1 Inclusion Criteria 29
III.2.2.2 Exclusion Criteria 29
III.2.2.3. Clinical Examination 29
III.2.2.4. Sample Collection 30
III.2.2.5 Minimum samples required 30
III.3. Work-flow 30
III.3.1 General 30
III.4 Collected Data 31
III.4.1 Primary Data 31
III.4.2. Secondary Data 31
III.5 Data analysis 31
III.6. Ethical Implication 31
CHAPTER IV. RESULTS AND DISCUSSION 33
IV.1 Clinical Findings 33
IV.2 Conventional Cytogenetic analysis 34
IV.3 Fragile-X exclusion test 34
IV.4 Linkage Analysis 34
IV.5 X-Chromosome Inactivation Analysis 35
IV.6 Mutation analysis in Candidate Genes 36
IV.7 Results and discussion for each family 37
Syndromic XLMR Families Family W92-053 XLMR and hypomyelination family
37 Family P03-0452 and 13753HC XLMR with Hydrocephalus families
44 Family W07-604
53 Family DF27004 MR and Overgrowth Features
57
Non Syndromic XLMR Families W09-0071
W09-0072 W09-0074
W09-0078 W08-2152
62 62
66 68
71 74
CHAPTER V CONCLUSION AND SUGGESTION
