Genomics of Rare Diseases: Understanding Disease Genetics Using Genomic Approaches

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
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