Genomics of Rare Diseases: Understanding Disease Genetics Using Genomic Approaches (Translational and Applied Genomics)

__Genomics of Rare Diseases: Understanding Disease Genetics Using Genomic Approaches__, a new volume in the __Translational and Applied Genomics__ series, offers readers a broad understanding of current knowledge on rare diseases through a genomics lens. This clear understanding of the latest molecular and genomic technologies used to elucidate the molecular causes of more than 5,000 genetic disorders brings readers closer to unraveling many more that remain undefined and undiscovered. The challenges associated with performing rare disease research are also discussed, as well as the opportunities that the study of these disorders provides for improving our understanding of disease architecture and pathophysiology. Leading chapter authors in the field discuss approaches such as karyotyping and genomic sequencing for the better diagnosis and treatment of conditions including recessive diseases, dominant and X-linked disorders, de novo mutations, sporadic disorders and mosaicism. Front Cover Genomics of Rare Diseases Copyright Page Contents List of contributors About the editors Preface References Acknowledgments 1 Introduction to concepts of genetics and genomics 1.1 Introduction 1.2 The human genome: structure and function 1.3 Genetic variation 1.4 Nomenclature in human genetics and genomics 1.5 Mendelian patterns of inheritance 1.6 Other modes of inheritance 1.7 Considerations of Mendelian disorders and genetic inheritance 1.8 Conclusion Further reading 2 Karyotyping as the first genomic approach 2.1 Introduction 2.2 Numerical chromosome aberrations 2.2.1 Autosomal aneuploidy 2.2.2 Sex chromosome aneuploidy 2.3 Structural chromosome aberrations 2.3.1 Reciprocal translocations 2.3.2 Paracentric and pericentric inversions 2.3.3 Robertsonian translocations 2.3.4 Deletions and duplications 2.3.5 Intrachromosomal and interchromosomal insertions 2.3.6 Isochromosomes 2.3.7 Marker chromosomes 2.3.8 Complex rearrangements and chromothripsis 2.4 Uniparental disomy and genomic imprinting 2.5 Clinical indications and special considerations for chromosome analysis References 3 Genomic disorders in the genomics era 3.1 Introduction 3.2 Chromosomal microarray analysis for copy-number variant detection and diagnosis of genomic disorders 3.3 The evolution of next-generation sequencing and bioinformatics for the detection of genomic rearrangements 3.4 Molecular mechanisms of genomic rearrangement generation 3.5 Genomic disorders and next-generation sequencing-based testing in the clinic 3.6 Interpretation of genomic structural and copy-number variants 3.7 Outlook References 4 Genomic sequencing of rare diseases 4.1 Introduction: a human genome reference sequence 4.2 Sequencing of genomes and exomes 4.3 The process of genomic sequencing 4.3.1 DNA preparation 4.3.2 Library preparation 4.3.3 Sequencing 4.3.4 Data analysis 4.4 Overview of sequencing technologies 4.4.1 First generation sequencing 4.4.2 Second generation sequencing technologies 4.4.3 Third generation sequencing technologies 4.5 Sequence data analysis 4.6 Genomic databases 4.7 Genomic sequencing of rare diseases 4.7.1 Large-scale genomic sequencing projects for rare diseases 4.7.2 Genomic sequencing in the clinic 4.8 Outlook References 5 Recessive diseases and founder genetics 5.1 Introduction 5.2 Autosomal recessive inheritance 5.2.1 The role of consanguinity in recessive diseases 5.2.2 The founder effect 5.2.3 Hardy–Weinberg equilibrium and inbreeding 5.3 Disease gene mapping of autosomal recessive disorders 5.3.1 Homozygosity mapping in consanguineous pedigrees 5.3.2 Genomic sequencing of rare recessive disorders 5.3.3 Genomics of founder populations 5.4 Outlook References 6 Dominant and sporadic de novo disorders 6.1 Introduction 6.2 Autosomal dominant disorders 6.2.1 Mechanisms of dominant disease 6.2.2 Incomplete penetrance and variable expressivity of dominant disorders 6.3 Sporadic disorders 6.3.1 The human de novo mutation rate 6.3.2 Mechanisms of disease of de novo mutations 6.3.3 Genomic studies of sporadic disorders and identification of de novo mutations 6.4 Outlook References 7 X-linked and mitochondrial disorders 7.1 Introduction 7.2 X Chromosome disorders 7.2.1 X-linked recessive disorders 7.2.2 X-linked dominant disorders 7.2.3 X chromosome inactivation as a modifier of X-linked disorders 7.3 Mitochondrial disorders 7.4 Outlook References 8 Mosaicism in rare disease 8.1 Introduction 8.1.1 Rate of somatic mutations 8.2 Strategies/technologies to identify mosaic variation 8.2.1 Clinical observation 8.2.2 Cytogenetics 8.2.3 Array comparative genome hybridization 8.2.4 Single nucleotide polymorphism arrays 8.2.5 Next-generation sequencing to identify mosaic variants 8.2.6 Mosaic disease in ClinVar 8.3 Mosaic aneuploidy in rare disease 8.3.1 Introduction to aneuploidy 8.3.2 General principles of mosaic aneuploidy 8.3.3 Mosaic autosome aneuploidies 8.3.3.1 Trisomy 1 mosaicism 8.3.3.2 Trisomy 2 mosaicism 8.3.3.3 Trisomy 3 mosaicism 8.3.3.4 Trisomy 4 mosaicism 8.3.3.5 Trisomy 5 mosaicism 8.3.3.6 Trisomy 6 mosaicism 8.3.3.7 Trisomy 7 mosaicism 8.3.3.8 Trisomy 8 mosaicism 8.3.3.9 Trisomy 9 mosaicism 8.3.3.10 Trisomy 10 mosaicism 8.3.3.11 Trisomy 11 mosaicism 8.3.3.12 Trisomy 12 mosaicism 8.3.3.13 Trisomy 13 mosaicism 8.3.3.14 Trisomy 14 mosaicism 8.3.3.15 Trisomy 15 mosaicism 8.3.3.16 Trisomy 16 mosaicism 8.3.3.17 Trisomy 17 mosaicism 8.3.3.18 Trisomy 18 mosaicism 8.3.3.19 Trisomy 19 mosaicism 8.3.3.20 Trisomy 20 mosaicism 8.3.3.21 Trisomy 21 mosaicism 8.3.3.22 Trisomy 22 mosaicism 8.3.4 Mosaic disorders of chromosome X 8.3.5 Mosaic disorders of chromosome Y 8.3.6 Variegated mosaic aneuploidy 8.3.7 Ring chromosomes 8.3.8 Mitochondrial genome mosaicism 8.3.9 Mosaic mobile element insertions 8.4 Categories of mosaic variation 8.4.1 Germline mosaicism 8.4.2 Cryptic mosaicism 8.5 Obligate mosaicism in rare disease 8.5.1 GNAS and McCune–Albright syndrome 8.5.2 Proteus syndrome 8.5.3 PIK3CA and CLOVES syndrome 8.5.4 GNAQ and Sturge–Weber syndrome 8.5.5 TSC1, TSC2, and the tuberous sclerosis complex 8.6 Cancer as a series of rare mosaic diseases 8.6.1 Somatic single nucleotide variants in cancer 8.6.2 Clonal evolution and cancer field effect (field cancerization) 8.6.3 Somatic mutations along lines of Blaschko 8.7 Mendelian disorders in mosaic form 8.7.1 Neurofibromatosis type I 8.7.2 Incontinentia pigmenti 8.7.3 Darier–White disease 8.7.4 Hereditary hemorrhagic telangiectasia 8.8 Chimerism 8.9 Outlook References 9 Multilocus inheritance and variable disease expressivity in rare disease 9.1 Introduction 9.2 Dual molecular diagnoses 9.2.1 Delineating dual molecular diagnoses 9.2.2 Dual molecular diagnoses lead to syndrome disintegration 9.2.3 Agnostic molecular techniques reveal multiple molecular diagnoses 9.2.4 Dissecting dual molecular diagnoses 9.3 Phenotypic expansion 9.3.1 Delineating phenotypic spectrum and expansion 9.3.2 Multiple molecular diagnoses masquerading as phenotypic expansion 9.3.3 Dissection of genotype–phenotype relationships through intrafamilial genotypic and phenotypic variability 9.4 Variable expressivity 9.4.1 Variable expressivity may portend mutational burden 9.5 Incomplete penetrance 9.5.1 Rare + common alleles at a single locus explain some cases of incomplete penetrance 9.5.2 Rare + common alleles at unlinked loci explain some cases of incomplete penetrance 9.6 A comprehensive model: Clan Genomics References 10 Statistical approaches to rare disease analyses 10.1 Introduction 10.2 Pedigree-based statistical methods 10.2.1 Linkage analysis 10.2.2 Transmission disequilibrium testing 10.3 Association analyses for rare diseases 10.3.1 Rare variant association testing in phenotype ascertained studies 10.3.2 Rare variant association testing of unascertained population-based studies 10.4 Conclusion References 11 Transcriptomics in rare diseases 11.1 Introduction 11.2 The transcriptome and transcriptomic methodologies 11.3 Transcriptomics in rare diseases 11.3.1 Mechanisms underlying RNA-seq-based genetic diagnoses 11.3.2 Transcriptomic analysis highlights disease modifiers 11.3.3 Tools for transcriptomics analyses in rare disease diagnosis 11.4 Single-cell resolution transcriptomics 11.5 Limitations of using RNA-seq in clinical molecular diagnosis References 12 Other omics approaches to the study of rare diseases 12.1 Introduction 12.2 Epigenomics 12.2.1 Definition of epigenetics and epigenomics 12.2.2 DNA methylation as the most prominent epigenetic mechanism 12.3 Landscape of epigenomic technologies 12.3.1 DNA methylation 12.3.2 Modification of chromatin states 12.3.3 Alternative methods to dissect chromatin modifications 12.3.4 Single-cell ChIP-seq 12.4 Dissecting chromatin structures 12.4.1 Profiling nucleosome positioning and chromatin accessibility 12.4.2 Evaluating higher-order chromatin architecture 12.5 Epigenomic studies in rare diseases 12.6 Proteomics 12.6.1 Protein arrays for biomarker discovery 12.6.2 Bottom-up and top-down proteomics approaches 12.6.3 Proteomics approaches to study rare diseases 12.7 Metabolomics 12.7.1 Metabolomics workflow and data analysis 12.7.2 Untargeted versus targeted metabolomics 12.7.3 Metabolomics studies in rare diseases 12.8 Outlook References 13 Challenges and opportunities in rare diseases research 13.1 Introduction 13.2 Challenges in rare diseases research 13.2.1 The N=1 Problem 13.2.2 Underrepresentation of non-European genetic ancestries 13.2.3 Unequal access to genomic initiatives aimed at understanding health and disease 13.2.4 Genetic heterogeneity, clinical variability, and phenotypic expansion of rare diseases 13.2.5 Insufficient knowledge of gene and genome function 13.3 Opportunities in rare diseases research 13.3.1 Insights into novel biology 13.3.2 Therapy development for rare diseases 13.3.3 Implementation of precision medicine and population health 13.3.4 Drug development derived from rare diseases insights 13.4 Outlook References Index Back Cover Genomics of Rare Diseases: Understanding Disease Genetics Using Genomic Approaches, a new volume in the Translational and Applied Genomics series, offers readers a broad understanding of current knowledge on rare diseases through a genomics lens. This clear understanding of the latest molecular and genomic technologies used to elucidate the molecular causes of more than 5,000 genetic disorders brings readers closer to unraveling many more that remain undefined and undiscovered. The challenges associated with performing rare disease research are also discussed, as well as the opportunities that the study of these disorders provides for improving our understanding of disease architecture and pathophysiology. Leading chapter authors in the field discuss approaches such as karyotyping and genomic sequencing for the better diagnosis and treatment of conditions including recessive diseases, dominant and X-linked disorders, de novo mutations, sporadic disorders and mosaicism. Compiles applied case studies and methodologies, enabling researchers, clinicians and healthcare providers to effectively classify DNA variants associated with disease and patient phenotypes Discusses the main challenges in studying the genetics of rare diseases through genomic approaches and possible or ongoing solutions Explores opportunities for novel therapeutics Features chapter contributions from leading researchers and clinicians