From Gene to Function to Clinic (13)

Question 1

Mary-Claire King

Answer 1

• Identified BRCA
• Humans and chimpanzees 99% genetically identical
• Applying genomic sequencing to identify victims of human rights abuses

Question 2

BRCA 1 and 2

Answer 2

Increases risk of breast cancer to 85% by 70, increases risk of developing ovarian cancer 2 > 55% (BRCA1) and 25% (BRCA2)

Question 3

Advantages testing BRCA mutations

Answer 3

• Relief
• Better response if specific BRCA treatment
• Preventative measures - tamoxifen
• Other family members may get tested

Question 4

Disadvantages testing BRCA mutations

Answer 4

• Worried
• Tell family members
• Test negative might think never get breast cancer
• Test positive - life/health insurance problems

Question 5

Prophylactic surgery

Answer 5

• Remove ovaries reduces risk by 85%

- Preventative mastectomy reduces risk by 90%

Question 6

Pre-symptomatic screening

Answer 6

Predict but can’t prevent, late onset disorders - Huntington’s, Retinitis pigments, Breast cancer, colon cancer

Question 7

Treacher Collins syndrome

Answer 7

Crania-Facial demorphology syndrome - failure of neural crest cells to migrate and form structures of face

Question 8

Symptoms of Treacher Collins syndrome

Answer 8

Small chin, narrowed constricted airways > tracheotomy, ‘man with sad eyes’

Question 9

Pre-natal screening for Treacher Collins syndrome

Answer 9

Immediately put in breathing tube

Question 10

Prenatal diagnosis

Answer 10

• Amniocentesis (17 weeks)
• Chorionic villus sampling (11 weeks)
• Maternal peripheral blood (sex)
• New non-invasive method based on NGS of mothers blood (10 weeks)

Question 11

Preimplantation diagnosis

Answer 11

Non-disclosure testing (without disease status of parents, Huntingtons) or HLA typing to match cord blood stem cells for siblings

Question 12

Problems associated with obesity

Answer 12

Coronary artery diseases, high blood pressure, type 2 diabetes, osteoarthritis, certain cancers

Question 13

Percentage of people overweight

Answer 13

46% men, 32% women

Question 14

Percentage of additional people obese

Answer 14

17% men, 21% women

Question 15

Obesity and heritability

Answer 15

BMI 70-80% heritability

Question 16

Leptin

Answer 16

Hormone released from fat cell leads to decrease in food intake, increase in thermogenesis, an increase in physical activity which all lead to decrease in fat cell mass, can have leptin replacement therapy

Question 17

Gene therapy

Answer 17

Use of genetic material (DNA/RNA) as medicine

Question 18

Leber’s congenital amaurosis (LCA)

Answer 18

Recessive, rare inherited eye disorder, blindness at birth/infancy, accounts for 10-18% of all congenital blindness, 18 genes implicated

Question 19

Eye

Answer 19

Immune privileged and accessible for sub retinal injection

Question 20

LCA mutation

Answer 20

In RPE65, photons hit retina > retinol > retinal pigmented epithelium, enzyme converts it back where it can receive photon again, enzyme is defective > poor vision

Question 21

Problems with LCA therapy tests

Answer 21

Retina must be structurally norma, single gene loss of function, missense mutations only, amblyopia (lazy eye) may inhibit result)

Question 22

Pharmacogenetics

Answer 22

Correlation between effect of drugs and genetic constitution of patients

Question 23

What percentage of hospital admission are due to adverse drug response?

Answer 23

5-7%

Question 24

Cytochrome P450 oxidases

Answer 24

Multilane family of enzymes found in liver

Question 25

What are Cytochrome P450 oxidases involved in?

Answer 25

Metabolic elimination of most drugs and convert pro-drugs > active form e.g. codeine

Question 26

CYP2D6

Answer 26

Highly polymorphic cytochrome 450 family member, metabolises 25% of drugs

Question 27

What percentage of caucasians are non-metabolisers?

Answer 27

6-10%, no active CYP2D6

Question 28

What percentage of caucasians are ultra-rapid metabolisers?

Answer 28

7%, multiple copies of CYP2D6

Question 29

Tamoxifen metabolism

Answer 29

CYP2D6 rate limiting step converting tamoxifen > active metabolite/endoxifen