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Table of Contents Table of contents Acknowledgements I List of Figures III List of Tables XI List of Abbreviations XIV Summary XVI Part 1 Primary microcephaly 1 INTRODUCTION 1 1.1 Primary microcephaly (MCPH) 2 1.2 Structure of cerebral cortex 5 1.3 Development of cerebral cortex 7 1.4 Clinical features of primary microcephaly 8 1.5 MCPH genes and their function 10 1.5.1 Microcephalin (MCPH1) 10 1.5.2 Abnormal spindle like microcephaly associated (ASPM) 11 1.5.3 Cyclin dependent kinase5 regulatory associated protein (CDK5RAP2) 12 1.5.4 Centrosomal protein J (CENPJ) 13 1.5.5 STIL (SCL/TAL1 interrupting locus) 13 1.6 Objectives of study 16 2 MATERIALS AND METHODS 17 2.1 Families studied 17 2.1.1 MCP3 18 2.1. 2 MCP6 19 2.1.3 MCP7 20 2.1.4 MCP9 21 2.1.5 MCP11 22 2.1.6 MCP15 23 2.1. 7 MCP17 24 2.1.8 MCP18 25 2.1.9 MCP21 26 2.1.10 MCP22 27 2.1.11 MCP35 28 2.1.12 MCP36 29 2.2 Clinical data 29 2.3 Blood sampling 32 2.4 DNA extraction 33 2.5 Polymerase chain reaction 33 2.6 Agarose gel electrophoresis 33 2.7 Genotyping using fluorescently labeled primers 34 2.8 Preparation of samples for ABI 3130xl genetic analyzer 35 2.9 Linkage analysis 35 2.10 Mutation screening 36 2.10.1 DNA sequencing 36 2.10.2 Purification of PCR product from agarose gel 37 2.10.3 Purification of PCR product 37 2.10.4 Sequencing PCR reactions 37 2.10.5 Precipitation of sequencing PCR products 38 2.10.6 Sequencing data analysis 38 2.11 Restriction analysis 39 3 RESULTS 51 3.1 Linkage studies 51 3.2 Mutation analysis 52 3.2.1 Sequencing of ASPM in MCPH5 linked families 52 3.2.2 Compound heterozygous ASPM mutations 53 3.2.2.1 Family MCP18 53 3.2.2.2 Family MCP35 53 3.2.3 Sequencing of CENPJ 54 3.2.4 Mutation screening in control population 54 3.2.5 Family MCP15 54 3.2.6 Sequencing of candidate genes in MCPH2 region 55 3.2.7 Sequencing of MCPH1 56 4 DISCUSSION 71 Part 2 Inherited limb disorders 5 INTRODUCTION 79 5.1 Polydactyly 79 5.2 Types of polydactyly 80 5.2.1 Preaxial polydactyly (PPD) 80 5.2.1.1 Thumb polydactyly (PPD1, OMIM: 174400) 80 5.2.1.2 Polydactyly of triphalangeal thumb (PPD2/TPT; OMIM: 174500) 80 5.2.1.3 Index finger polydactyly (polydactyly, Preaxial III, OMIM: 174600) 81 5.2.1.4 Preaxial polydactyly type IV (PPD IV, OMIM: 174700) 81 5.2.2 Postaxial polydactyly (PAP) 82 5.2.2.1 Postaxial polydactyly type A (PAPA) 82 5.2.2.2 Postaxial polydactyly type B (PAPB, OMIM: 174200) 82 5.3 Brachydactyly 83 5.3.1 Brachydactyly type A 84 5.3.1.1 Brachydactyly type A1 (BDA1; OMIM: 112500) 84 5.3.1.2 Brachydactyly type A2 (BDA2; OMIM: 112600) 84 5.3.1.3 Brachydactyly type A3 (BDA3; OMIM: 112700) 85 5.3.1.4 Brachydactyly type A4 (BDA4; OMIM: 112800) 85 5.3.1.5 Brachydactyly type A5 (BDA5; OMIM: 112900) 85 5.3.2 Brachydactyly type B (BDB; OMIM: 113000) 86 5.3.3 Brachydactyly type C (BDC; OMIM: 113100) 86 5.3.4 Brachydactyly type D (BDD; OMIM: 113200) 87 5.3.5 Brachydactyly type E (BDE; OMIM: 113300) 87 5.3.6 Brachymetatarsus IV (OMIM: 113475) 88 5.3.7 Sugarman brachydactyly (OMIM: 272150) 88 5.3.8 Kirner deformity (OMIM: 128000) 88 5.3.9 Brachydactyly as a part of syndrome 89 5.4 Syndactyly 90 5.4.1 Classification of syndactylies 90 5.4.1.1 Syndactyly Type I (SD1; MIM 185900) 91 5.4.1.2 Syndactyly Type II, Synpolydactyly (SPD; MIM 186000) 91 5.4.1.3 Syndactyly Type III (MIM 186100) 92 5.4.1.4 Syndactyly Type IV, Haas Type Syndactyly (MIM 186200) 93 5.4.1.5 Syndactyly Type V (MIM 186300) 93 5.4.1.6 Syndactyly Type VI, Mitten syndactyly 93 5.4.1.7 Syndactyly Type VII, Cenani-Lenz Syndactyly (MIM 212780) 94 5.4.1.8 Syndactyly Type VIII 94 5.4.1.9 Syndactyly Type IX, Malik-Percin type syndactyly 94 5.5 Syndromic hand anomalies 94 5.5.1 Greig cephalopolysyndactyly syndrome 94 5.6 Limb development 96 6 MATERIALS AND METHODS 97 6.1 Methods 97 6.1.1 Nuclear extract preparation 97 6.1.2 Annealing of probes for EMSA 98 6.1.3 Radioactive labelling of double stranded EMSA probes 98 6.1.4 Electrophoretical mobility shift assay (EMSA) procedure 98 6.1.5 Genome wide linkage analysis 99 6.1.6 Candidate gene search 99 6.1.7 Copy number variation detection 100 6.2 Families studied 101 6.2.1 Family PD1 101 6.2.2 Family PD2 103 6.2.3 Family PD316 107 6.2.4 Family PD7 109 6.2.5 Family PD16 111 6.2.7 Family BD1 113 6.2.7.1 Clinical description 114 6.2.8 Syndactyly families 116 6.2.8.1 Family PD14A 117 7 RESULTS AND DISCUSSION 129 7.1 Family PD1 129 7.1.1 Linkage analysis and Mutation detection 129 7.1.2 Electrophoretic mobility shift assay 129 7.1.3 Discussion 134 7.2 Family PD2 136 7.2.1 Linkage analysis and Mutation detection 136 7.3 Family PD316 139 7.4 Family PD7 141 7.5 Family PD16 143 7.6 Discussion 145 7.3 Family BD1 148 7.3.1 Exclusion of locus on 2q31 (HOXD13) for brachydactyly type E 148 7.3.2 Genome-wide search using 10K SNP array and fine mapping 148 7.3.3 Mutation screening 145 7.3.4 Genome wide SNP array 6.0 analysis to detect copy number variation 150 7.3.5 Discussion 156 7.4 Family PD14A 157 7.4.1 Novel isolated autosomal recessive 2nd and 3rd digit syndactyly 157 7.4.2 Exclusion studies and Genome wide linkage analysis 157 7.4.3 Sequencing of candidate gene 158 7.4.4 Discussion 164 REFERENCES 166 Appendix .
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