Precision Medicine: A Guide to Genomics in Clinical Practice

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