فهرست مطالب:

List of contributors .......xiii
About the editors .......xv
Preface .......xvii
Acknowledgments .......xxi
CHAPTER 1 Introduction to concepts of genetics and genomics.......1
Karlla Welch Brigatti
1.1 Introduction .......1
1.2 The human genome: structure and function.......1
1.3 Genetic variation .......5
1.4 Nomenclature in human genetics and genomics .......8
1.5 Mendelian patterns of inheritance .......9
1.6 Other modes of inheritance.......12
1.7 Considerations of Mendelian disorders and genetic inheritance .......14
1.8 Conclusion.......15
Further reading .......15
CHAPTER 2 Karyotyping as the first genomic approach.......17
Amy Breman and Paweł Stankiewicz
2.1 Introduction .......17
2.2 Numerical chromosome aberrations .......19
2.2.1 Autosomal aneuploidy .......21
2.2.2 Sex chromosome aneuploidy.......21
2.3 Structural chromosome aberrations .......22
2.3.1 Reciprocal translocations .......22
2.3.2 Paracentric and pericentric inversions.......23
2.3.3 Robertsonian translocations .......23
2.3.4 Deletions and duplications.......25
2.3.5 Intrachromosomal and interchromosomal insertions .......25
2.3.6 Isochromosomes.......26
2.3.7 Marker chromosomes.......27
2.3.8 Complex rearrangements and chromothripsis .......28
2.4 Uniparental disomy and genomic imprinting .......28
2.5 Clinical indications and special considerations for chromosome analysis.......30
References.......31
v
CHAPTER 3 Genomic disorders in the genomics era.......35
Cinthya J. Zepeda Mendoza and Claudia Gonzaga-Jauregui
3.1 Introduction .......35
3.2 Chromosomal microarray analysis for copy-number variant detection and
diagnosis of genomic disorders.......38
3.3 The evolution of next-generation sequencing and bioinformatics for the
detection of genomic rearrangements.......40
3.4 Molecular mechanisms of genomic rearrangement generation.......42
3.5 Genomic disorders and next-generation sequencing-based testing
in the clinic.......45
3.6 Interpretation of genomic structural and copy-number variants.......47
3.7 Outlook .......48
References.......49
CHAPTER 4 Genomic sequencing of rare diseases.......61
Claudia Gonzaga-Jauregui and Cinthya J. Zepeda Mendoza
4.1 Introduction: a human genome reference sequence .......61
4.2 Sequencing of genomes and exomes .......63
4.3 The process of genomic sequencing.......65
4.3.1 DNA preparation.......65
4.3.2 Library preparation .......65
4.3.3 Sequencing .......68
4.3.4 Data analysis .......68
4.4 Overview of sequencing technologies .......68
4.4.1 First generation sequencing .......71
4.4.2 Second generation sequencing technologies .......71
4.4.3 Third generation sequencing technologies .......73
4.5 Sequence data analysis.......74
4.6 Genomic databases.......79
4.7 Genomic sequencing of rare diseases.......83
4.7.1 Large-scale genomic sequencing projects for rare diseases .......84
4.7.2 Genomic sequencing in the clinic .......86
4.8 Outlook .......87
References.......88
CHAPTER 5 Recessive diseases and founder genetics .......97
Erik G. Puffenberger
5.1 Introduction .......97
5.2 Autosomal recessive inheritance.......97
vi Contents
5.2.1 The role of consanguinity in recessive diseases .......100
5.2.2 The founder effect.......101
5.2.3 HardyWeinberg equilibrium and inbreeding.......104
5.3 Disease gene mapping of autosomal recessive disorders.......106
5.3.1 Homozygosity mapping in consanguineous pedigrees .......106
5.3.2 Genomic sequencing of rare recessive disorders .......109
5.3.3 Genomics of founder populations.......110
5.4 Outlook .......112
References.......112
CHAPTER 6 Dominant and sporadic de novo disorders .......117
Claudia Gonzaga-Jauregui, Lauretta El Hayek and Maria Chahrour
6.1 Introduction .......117
6.2 Autosomal dominant disorders .......118
6.2.1 Mechanisms of dominant disease .......118
6.2.2 Incomplete penetrance and variable expressivity of dominant disorders.......123
6.3 Sporadic disorders .......124
6.3.1 The human de novo mutation rate.......124
6.3.2 Mechanisms of disease of de novo mutations.......126
6.3.3 Genomic studies of sporadic disorders and identification of
de novo mutations.......128
6.4 Outlook .......131
References.......131
CHAPTER 7 X-linked and mitochondrial disorders .......137
Lauretta El Hayek and Maria Chahrour
7.1 Introduction .......137
7.2 X Chromosome disorders.......138
7.2.1 X-linked recessive disorders.......138
7.2.2 X-linked dominant disorders .......139
7.2.3 X chromosome inactivation as a modifier of X-linked disorders.......141
7.3 Mitochondrial disorders .......142
7.4 Outlook .......145
References.......146
CHAPTER 8 Mosaicism in rare disease.......151
Bracha Erlanger Avigdor, Ikeoluwa A. Osei-Owusu and
Jonathan Pevsner
8.1 Introduction .......151
8.1.1 Rate of somatic mutations .......153
8.2 Strategies/technologies to identify mosaic variation.......153
8.2.1 Clinical observation .......155
Contents vii
8.2.2 Cytogenetics.......155
8.2.3 Array comparative genome hybridization .......156
8.2.4 Single nucleotide polymorphism arrays .......156
8.2.5 Next-generation sequencing to identify mosaic variants .......156
8.2.6 Mosaic disease in ClinVar.......158
8.3 Mosaic aneuploidy in rare disease.......158
8.3.1 Introduction to aneuploidy.......158
8.3.2 General principles of mosaic aneuploidy .......163
8.3.3 Mosaic autosome aneuploidies .......163
8.3.4 Mosaic disorders of chromosome X.......167
8.3.5 Mosaic disorders of chromosome Y.......167
8.3.6 Variegated mosaic aneuploidy.......168
8.3.7 Ring chromosomes.......168
8.3.8 Mitochondrial genome mosaicism.......168
8.3.9 Mosaic mobile element insertions .......169
8.4 Categories of mosaic variation .......169
8.4.1 Germline mosaicism .......169
8.4.2 Cryptic mosaicism .......170
8.5 Obligate mosaicism in rare disease .......170
8.5.1 GNAS and McCuneAlbright syndrome .......170
8.5.2 Proteus syndrome.......171
8.5.3 PIK3CA and CLOVES syndrome.......171
8.5.4 GNAQ and SturgeWeber syndrome.......171
8.5.5 TSC1, TSC2, and the tuberous sclerosis complex.......174
8.6 Cancer as a series of rare mosaic diseases .......174
8.6.1 Somatic single nucleotide variants in cancer .......175
8.6.2 Clonal evolution and cancer field effect (field cancerization) .......175
8.6.3 Somatic mutations along lines of Blaschko .......175
8.7 Mendelian disorders in mosaic form .......175
8.7.1 Neurofibromatosis type I .......176
8.7.2 Incontinentia pigmenti .......176
8.7.3 DarierWhite disease.......176
8.7.4 Hereditary hemorrhagic telangiectasia .......176
8.8 Chimerism .......177
8.9 Outlook .......177
References.......177
CHAPTER 9 Multilocus inheritance and variable disease expressivity
in rare disease.......185
Jennifer E. Posey
9.1 Introduction .......185
viii Contents
9.2 Dual molecular diagnoses .......186
9.2.1 Delineating dual molecular diagnoses.......186
9.2.2 Dual molecular diagnoses lead to syndrome disintegration .......186
9.2.3 Agnostic molecular techniques reveal multiple molecular diagnoses.......187
9.2.4 Dissecting dual molecular diagnoses.......189
9.3 Phenotypic expansion.......192
9.3.1 Delineating phenotypic spectrum and expansion.......192
9.3.2 Multiple molecular diagnoses masquerading as phenotypic expansion .......193
9.3.3 Dissection of genotypephenotype relationships through intrafamilial
genotypic and phenotypic variability .......193
9.4 Variable expressivity.......194
9.4.1 Variable expressivity may portend mutational burden .......194
9.5 Incomplete penetrance .......195
9.5.1 Rare 1 common alleles at a single locus explain some cases of
incomplete penetrance .......196
9.5.2 Rare 1 common alleles at unlinked loci explain some cases of
incomplete penetrance .......197
9.6 A comprehensive model: Clan Genomics .......198
References.......200
CHAPTER 10 Statistical approaches to rare disease analyses.......205
Cristopher V. Van Hout
10.1 Introduction .......205
10.2 Pedigree-based statistical methods .......205
10.2.1 Linkage analysis.......205
10.2.2 Transmission disequilibrium testing.......207
10.3 Association analyses for rare diseases.......208
10.3.1 Rare variant association testing in phenotype ascertained studies .......208
10.3.2 Rare variant association testing of unascertained population-based
studies.......211
10.4 Conclusion.......212
References.......212
CHAPTER 11 Transcriptomics in rare diseases .......215
Maria Kousi
11.1 Introduction .......215
11.2 The transcriptome and transcriptomic methodologies .......217
11.3 Transcriptomics in rare diseases.......218
11.3.1 Mechanisms underlying RNA-seq-based genetic diagnoses.......218
11.3.2 Transcriptomic analysis highlights disease modifiers.......223
11.3.3 Tools for transcriptomics analyses in rare disease diagnosis .......224
Contents ix
11.4 Single-cell resolution transcriptomics.......224
11.5 Limitations of using RNA-seq in clinical molecular diagnosis.......225
References.......226
CHAPTER 12 Other omics approaches to the study of rare diseases .......229
Giusy Della Gatta
12.1 Introduction .......229
12.2 Epigenomics .......229
12.2.1 Definition of epigenetics and epigenomics .......229
12.2.2 DNA methylation as the most prominent epigenetic mechanism .......230
12.3 Landscape of epigenomic technologies .......232
12.3.1 DNA methylation.......232
12.3.2 Modification of chromatin states.......233
12.3.3 Alternative methods to dissect chromatin modifications.......233
12.3.4 Single-cell ChIP-seq .......234
12.4 Dissecting chromatin structures.......235
12.4.1 Profiling nucleosome positioning and chromatin accessibility.......235
12.4.2 Evaluating higher-order chromatin architecture.......236
12.5 Epigenomic studies in rare diseases .......237
12.6 Proteomics .......238
12.6.1 Protein arrays for biomarker discovery .......239
12.6.2 Bottom-up and top-down proteomics approaches.......240
12.6.3 Proteomics approaches to study rare diseases.......242
12.7 Metabolomics .......243
12.7.1 Metabolomics workflow and data analysis .......244
12.7.2 Untargeted versus targeted metabolomics.......246
12.7.3 Metabolomics studies in rare diseases.......246
12.8 Outlook .......248
References.......249
CHAPTER 13 Challenges and opportunities in rare diseases research.......263
Claudia Gonzaga-Jauregui
13.1 Introduction .......263
13.2 Challenges in rare diseases research.......264
13.2.1 The N 5 1 Problem .......264
13.2.2 Underrepresentation of non-European genetic ancestries.......266
13.2.3 Unequal access to genomic initiatives aimed at understanding
health and disease .......268
13.2.4 Genetic heterogeneity, clinical variability, and phenotypic
expansion of rare diseases .......269
13.2.5 Insufficient knowledge of gene and genome function.......270
x Contents
13.3 Opportunities in rare diseases research .......272
13.3.1 Insights into novel biology .......272
13.3.2 Therapy development for rare diseases.......272
13.3.3 Implementation of precision medicine and population health.......275
13.3.4 Drug development derived from rare diseases insights .......276
13.4 Outlook .......278
References.......279
Index .......285

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