Diagnostic Genetic Testing: Core Concepts and the Wider Context for Human DNA Analysis

Foreword
Preface
Further Reading
Laboratory Techniques
Genetic Disorders
General Overviews of Genomic Testing in Healthcare
Patient Support Groups
Acknowledgements
Contents
About the Author
Abbreviations
1 Genetic Testing, Some Themes and Some Basics
	Genetic Testing
	Complexity: Genes and Environment
	Risk and Uncertainty
	DNA and Categorisation
	Future Promises and Concerns
	Genetics in Other Areas of Medicine
	Basic Concepts in Genetics
	DNA Stores Information that Can Be Copied
	Genomic Architecture
	Gene Function and Organisation Within Genomes
	Transcription, Translation and the Genetic Code
	Mutation
	Patterns of Inheritance: Autosomal Dominant and Autosomal Recessive
	X-linked Inheritance
	Some Basics of Genetic Testing
	Isolation of DNA
	Finding Mutations
	Finding a Complementary Sequence
	The Polymerase Chain Reaction and DNA Amplification
	Electrophoresis
	DNA Sequencing
2 Autosomal Dominant Inheritance and Huntington Disease
	Huntington Disease
	A Very Specific Genetic Error
	A Gain of Function
	Why Expansions?
	Determinism, but with Complications
	Anticipation
	Genetic Testing for HD
	Test Sensitivity and Specificity
	The Value of Genetic Testing for HD
	Laboratory Errors
	Genetic Information and Families
3 Autosomal Recessive Inheritance and Cystic Fibrosis
	Contrasting Dominant and Recessive Conditions
	Cystic Fibrosis
	Many Different Genetic Errors: Some with Variable Effects
	Common Recessive Disorders
	Genetic Testing for CF
	The Value of Genetic Testing in CF
	Prenatal Diagnosis
	Therapies for CF and Genetic Testing
	Calculating Risks
		Scenario 1
		Scenario 2
4 X-linked Inheritance: A Question of Gender
	A Fundamental Imbalance
	Switching Off Genes on the Inactive X Chromosome
	Inheritance of X-linked Genetic Disorders
	Three X-linked Genes Associated with Genetic Disorders
	X-linked Example 1: The DMD Gene and Duchenne Muscular Dystrophy/Becker Muscular Dystrophy
	The Spectrum and Significance of Mutations in the DMD Gene
	Testing for DMD Gene Mutations
	X-linked Example 2: The FMR1 Gene, Fragile X Syndrome and Other Phenotypes
	Multiple Conditions Are Associated with FMR1 Gene Mutations
	Transmission of Fragile X Syndrome
	Testing for FMR1 Gene Mutations
	X-linked Example 3: The Androgen Receptor (AR) Gene, Spinal and Bulbar Muscular Atrophy and Androgen Insensitivity Syndrome
	SBMA: A Trinucleotide Expansion Disorder
	AIS: Loss of Function Mutations in the AR Gene
	Genetics and Gender
5 Genetic Testing in Cancer
	Cancer as a Genetic Disease
	Inherited Cancer Predisposition
	Tumor Suppressor Genes
	BRCA1 and BRCA2 as Tumor Suppressor Genes
	Oncogenes
	Cytogenetics and Cancer Testing
	Chromosome Analysis
	The Philadelphia Chromosome
	Rapid Detection of Specific Gene Fusions and Other Chromosomal Rearrangements in Cancers by FISH
	Genetic Testing in Cancer Diagnosis and Treatment
6 DNA Testing, Genetics and Identity
	Identity Testing in the Diagnostic Genetic Laboratory
	Diagnostic Applications for Genetic Identity Testing
	Direct Testing of Identity
	Family Relationships
	Identity in Twins
	Avoiding Errors in Prenatal Diagnosis
	Monitoring Bone Marrow Transplants
	DNA as a Marker of Unique Personal Identity
	Widening Circles
	Identity as a Member of Humanity
7 Out of Sequence: Genome-Scale Testing
	Whole Genome Analyses
	Sanger Sequencing
	Diagnostic Sanger Sequencing Applications
	Next-Generation Sequencing (NGS)
	Diagnostic Applications of New Sequencing Technologies
	Trio Analysis and New Mutations
	Genomic Analysis in Cancer
	NGS, Clonal Sequencing and Finding a Needle in a Haystack
	Finding New Disease Associations
	Comparative Genomics
	Third-Generation (Long-Read) Sequencing
	Limitations to the Utility of Genome-Scale Sequencing
	Confounding Factors: Complexity of Common Disease
	Confounding Factors: Lots of Variation, Many Rare Variants
	Confounding Factors: Complex Metabolic Networks
	Epigenetic Regulation: A Further Level of Complexity
	The Risk of False Positives
	Will WGS Improve Outcomes for Common Disorders?
	Genomic Testing in Mainstream Medicine: Because We Can Rather Than Because We Should?
8 DNA Testing: Pulling the Strands Together
	Diagnostic Genetics and Ethical Principles
	Consent in the Genomic Era
	Making Genetic Choices
	Compartmentalisation on Genetic Grounds
	Commercial Access to Genetic Testing
	Acknowledging Uncertainties and Avoiding Error
	The Value of Genetic Testing
	The Language of Genetics: Uses and Misuses
	Genetics and Society