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Key Point: In this 10 month curriculum, well be discussing how to frame genomic information to provide personalized care to your patient in 4 specific skill sets. Details: Genomic information is just another tool that you can add to the skills you already have in these four areas of patient care Risk assessment: Assessing genomic load is a piece of overall risk assessment for disease Testing: Determine appropriate uses of testing that will reduce morbidity and mortality, using evidence base and guidelines where available Management: interpret and understand implications of test results, family history, and other genomic information Communicate: education, anticipatory guidance, assessment of values and needs, and psychosocial support

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Introduction
Focus on Variation

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Instructions: Introduce hypothetical scenario to frame discussion of variation

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Key Point: Genetic variation is the norm, and the source of human diversity NOTES Many variants have NO effect Many cause harmless changes (normal height or eye color variation) Polymorphism refers to a genetic region that exists in many common, benign forms, each occurring in at least 1% of the population. Variants that cause harmful changes in physiology (hemophilia) are rare Commonly called mutations, but pathologic variant is more accurate, and is the term we will be using

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Key Point: A variant is pathogenic when it affects the amount or function of a critical protein. NOTES For rare variants with strong association to disease, the functional effects are usually known Variants cause disease in two primary ways: Changes in the amount of the gene product (example: PKU & enzyme deficiency) Changes the function of the gene product (example: sickle cell anemia and altered protein shape) The functional effects of a variant inform clinical significance, including prognosis and treatment options, which we will discuss more later.

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Key Point: Susceptibility to environmental insults varies depending on the level of genetic predisposition. NOTES: Strong genetic contribution (high penetrance genes): Only small environmental insults are needed to manifest disease. Strong genetic contribution could be a single gene of large effect, or many genes of small effect added together. For those with mild genetic contribution, greater environmental exposure over a longer time is required to pass the threshold for disease. Example: individuals with genetic predisposition to cancer tend to develop tumors earlier in life than those with sporadic cancer

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Interactive Case Studies

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Neurogenomics

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Instructions: Ask for volunteers from small groups to share their answers to the discussion question. Use the next slide to answer and fill in gaps. Suggested prompts: How certain are you of the diagnoses in her relatives? How does the age of onset influence your estimate? Is APOE4 causative?

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Instructions: Use this slide to debrief from the last slide Key Point: APOE4 alleles are common in the general population and slightly more common in people with a close family history. Details: APOE4 alleles are also common in the general population. If Gaels mother had a APOE4 allele, Gael would have at least a 50% chance of having a E4 allele. If Gaels mother was homozygous for E4, Gael would carry at least 1 E4 allele. Seeing an autosomal dominant pattern of disease (mother and grandmother affected) does not always translate to a 50% risk. There is uncertainty about the diagnoses, especially in the grandmother, and limited information about other risk factors. Finally, AD is a very common condition in the population. Reference for family history numbers: Huang W, C Oiu, E von Strauss, B Winblad, L Fratiglioni. APOE Genotype, Family History of Dementia, and Alzheimer Disease Risk: A 6-Year Follow-up Study. Arch Neurol. 2004;61(12):1930-1934.

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Instructions: Ask for volunteers from each small group to share their answers to the discussion question. Use the next slide to answer.

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Instructions: Use the next 2 slides to debrief from the discussion. Use them to fill in gaps. Key Point: Having an E4 risk allele increases risk for Alzheimers disease. Details. Positive testing (E4/e4): increased, but APOE not necessary or sufficient for disease The E4 allele has been associated with AD, but no causal attribution has been made.

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Key Point: Even among E4/E4 carriers, nearly 50% of males and 40% of females do not develop AD. There are other environmental and genetic factors involved. Details: Age: After age 65, risk of developing AD doubles about every five years. Nearly half of those over age 85 have Alzheimer's. Sex: Women may be more likely than are men to develop Alzheimer's disease, in part because they live longer. Lifestyle: same factors that increase risk of heart disease may also increase AD risk. Lack of exercise, Smoking, High blood pressure, High cholesterol, Poorly controlled diabetes Family history: having a first degree relative with AD increases your risk from ~7% to ~26% cumulative lifetime risk. APOE4 does not explain all of the family history related risk. They may be independent risks in some families

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Small Group Practice

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Pharmacogenomics

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Instructions: Allow 15 minutes for participants to discuss the cases at their table. Afterwards, use the following slides to walk through each discussion question with the whole class one at a time. Ask for volunteers to share their small groups conclusions for each question. Each table will be provided with: Clinical scenario Background information on the CYP450 enzyme and SSRIs Data on validity of testing for CYP450 variants for SSRI response Discussion questions Note: This small group exercise is based on data from a few specific studies, which do not represent the entirety of current knowledge about this topic. The exercise is intended to teach how to interpret and apply PGx validity data in general. It is not intended to teach specific facts about psychiatric PGx.

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Instructions: Ask for volunteers to share their small groups conclusions for this question.

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Instructions: Debrief from large group discussion. Fill in gaps as needed Details: CYP2D6 variants are infrequent in the general population Data is poor for Hispanic populations

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Instructions: This question was not included in the small group discussion questions. Engage the large group in discussing it, based on the information they now know.

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Key Point: There are often redundant pathways, involving different enzymes, to the same metabolite Details: CYP2D6 is just one of the large CYP450 family of enzymes, and other enzyme families are also involved in drug metabolism. Each enzyme is influenced by different genetic (and non-genetic) factors. Alt image sources: http://www.doctorfungus.org/thedrugs/antif_interaction.php http://www.sciencedirect.com/science/article/pii/S0273230012000220

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Patient-Centered

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Prenatal/Pediatric

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Instructions: Prime the audience to listen for specific aspects of the story to be discussed afterwards

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Instructions: Engage the class in a discussion of the video, highlighting the psychosocial impact and risks of genetic diagnosis. Suggested prompts and follow-up questions: How did the diagnosis positively impact the family? How did it negatively impact the family? What concerns did this parent have about sharing the genetic diagnosis with others?

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Key Point: Diagnosis can be empowering, but also carries burdens.

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For more information

Kate Reed kreed@nchpeg.org 410-583-0600

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