Table of Contents

Chapters 1-4: Pregnancy and childhood

Chapter 1: Preconception

What are the applications of precision medicine in the preconception period?

• Infertility
• Carrier screening – traditional and expanded
• Genetic counselling, reimbursement, where to get tested
• Future prospects: Preimplantation genetic testing

Chapter 2: Pregnancy

What are the applications of precision medicine during pregnancy?

• Triple/quad screening
• Amniocentesis/CVS
• Trisomy testing using non-invasive (cfDNA) methods
• Future prospects: expanded uses of cfDNA testing during pregnancy

Chapter 3: The Newborn

What are the applications of precision medicine in the newborn period? What are the situations when a clinician should consider a genetic diagnosis, what tests are commonly used, what evaluation can be performed by the non-specialist versus when to refer to a specialist.

• Mandatory newborn screening
• Broad classification and evaluation of birth defects
• Broad classification and evaluation of metabolic disease
• Future prospects: Sequencing from birth

Chapter 4: Childhood and Adolescence

What are the applications of precision medicine during childhood and adolescence?

• Autism and Developmental delay
• Childhood cancer (hereditary cancer)
• Rare diseases and diagnostic sequencing
• Support and advocacy for rare diseases

Chapters 5-9: Adulthood

Chapter 5: Pharmacogenetics

What pharmacogenetic tests are available? How valid and useful are they?

• Types of pharmacogenetic markers
  • Efficacy-based, companion diagnostics
  • Safety-based, avoiding severe adverse events
  • Dosing-based
• Understanding CYP450 alleles
• Sources of information about pharmacogenetic tests
  • Drug labels
  • Evidence guidelines
  • PharmGKB, Dutch group

Chapter 6: Heart Disease

How is precision medicine being applied in heart disease?

• Predisposition/diagnostic testing for myocardial infarction, thrombosis risk, arrhythmias
• The utility of prognostic markers (e.g. CardioDx test)
• Managing dose, efficacy and side effects of cardiovascular drugs using pharmacogenomics
  • Clopidogrel, Warfarin, Simvastatin

Chapter 7: Infectious disease

How is precision medicine being applied in infectious disease?

• Managing dose, efficacy and side effects of ID drugs using pharmacogenomics

· Tracking outbreaks, pathogen discovery

· Future prospects: diagnostic sequencing

Chapter 8: Cancer

How is precision medicine being applied in cancer?

• Diagnostic/predisposition testing for Hereditary cancers
  • HBOC, Lynch Syndrome, rare hereditary cancer syndromes
• Managing dose, efficacy and side effects of cancer drugs using pharmacogenetics
  • Irinotecan, Belinostat, Azothioprine, Capecitaban, Tamoxifen, Oliparib
• The genetic landscape of tumors
• Prognostic markers
• Targeted treatment and companion diagnostics
• Tumor profiling and expanded treatment options
• Future prospects: cfDNA for screening, diagnosing and monitoring cancer

Chapter 9: The Brain - Mental Health and Neurodegeneration

How is precision medicine being applied in mental health and neurodegenerative disease?

• Predisposition/diagnostic testing for epilepsies, Alzheimer, Parkinson diseases
• Managing dose, efficacy and side effects of antidepressant, antipsychotic, anti-seizure drugs using pharmacogenomics

Appendices. Conceptual framework for understanding genomic and precision medicine

Appendix 1: Genome variation

Describes the structure and organization of the human genome and the different types of variation, their consequences and distribution in different populations

• DNA, RNA, Protein variation
• Origin and types of genetic (DNA) variation (from big to small)
• Consequences of genetic variation
• Patterns of genetic variation across populations and ancestry

Appendix 2: Laboratory methods to detect genome variation

A roadmap of different testing methods that a practitioner may come across, what they can measure, and what are their limitations. Includes sample test requisitions and reports with graphical interpretation.

• DNA variation (aCGH, karyotyping, FISH,Targeted genotyping, SNP arrays, Sanger and next-gen sequencing -whole genome, whole exome, panel)
• The unique mitochondrial genome
• RNA variation (QrtPCR, Transcript arrays, next-gen sequencing)
• Protein variation (IHC, mass spectrometry)
• Epigenome variation (Bisulfite sequencing)
• How to find a testing laboratory (general information, specifics discussed within each disease type)

Appendix 3: Genetic variation and disease

How is genetic variation related to disease?

• Inheritance patterns
• Penetrance, expressivity, environmental influences
• Family history: why it still matters

Appendix 4: Evidence base

How do we know if a gene-trait association is valid or clinically useful?

· Evaluating the evidence

o Establishing the role of the gene in disease

· Clinical validity (PPV, NPV)

· Clinical utility (cost effectiveness, comparative effectiveness)

· Where to find evidence, information and practice guidelines

How do we determine pathogenicity of variants in a diagnostic setting?

· Different types of evidence used in variant classification

· ACMG framework for variant classification

· Clinvar and other variant databases

Appendix 5: Regulation and reimbursement

How do regulation and reimbursement play a role in the delivery of precision medicine?

• US FDA and genetic testing
• Insurance coverage of genomic tests in the US

· Access to genetic testing

Appendix 6: Cross-cutting ethical issues

What key ethical issues to be aware of with genetic testing?

• Secondary/incidental findings
• Discrimination and GINA
• Privacy and sharing
• Testing minors
• Population screening
• Eugenics and disability rights
• How to gather appropriate informed consent

About the Author

Jeanette J. McCarthy, MPH, PhD (San Francisco, CA) Adjunct Associate Professor, University of California, San Francisco.

Bryce A. Mendelsohn, MD, PhD (San Francisco, CA) Medical Genetics Clinical Fellow, University of California, San Francisco.