Gene to Function to Clinic

Question 1

What are the breast cancer genes?

Answer 1

BRCA1 and BRCA2: The most common cause of hereditary breast cancer is an inherited mutation in the BRCA1 or BRCA2 gene. In normal cells, these genes help make proteins that repair damaged DNA. Mutated versions of these genes can lead to abnormal cell growth, which can lead to cancer.

Question 2

What % of breast cancers do mutations in BRCA1 and BRCA2 count for?

Answer 2

5-10%

Question 3

The average woman has 12% risk of developing breast cancer (by the time she is 90). How much does having the BRCA1 or BRCA2 mutation increase this risk?

Answer 3

Increases risk of breast cancer to 85% (70 years) ALSO Increases risk of developing ovarian cancer from <2% to 55% (BRCA1) and 25% (BRCA2)

Question 4

What is prophylactic surgery?

Answer 4

A form of surgery whose purpose is to minimise or prevent the risk of developing cancer in an organ or gland that has yet to develop cancer and is known to be at high risk of developing cancer. - Removing ovaries after family - Preventative mastectomy

Question 5

What is effect of removing ovaries on cancer risk?

Answer 5

Reduces risk by 85%

Question 6

What is effect of preventative mastectomy?

Answer 6

Reduces risk by 90%

Question 7

What is presymptomatic screening?

Answer 7

Types of testing are used to detect gene mutations associated with disorders that appear after birth, often later in life

Question 8

What type of diseases are screened for in presymptomatic screening?

Answer 8

Late onset disorders: - Huntington’s disease - Retinitis pigmentosa - Breast cancer - Colon cancer

Question 9

What is ‘penetrance’?

Answer 9

Penetrance refers to the proportion of people with a particular genetic change who exhibit signs and symptoms of a genetic disorder. Reduced penetrance –> people with the mutation do not develop features of the disorder

Question 10

What is non-penetrance?

Answer 10

People who have the mutation but don’t show the disease

Question 11

What is Treacher Collins Syndrome?

Answer 11

Craniofacial disorder (genetic) –> characterised by deformities of the ears, eyes, cheekbones, and chin. The degree to which a person is affected may vary from mild to severe (different penetrance)

Question 12

What is an amniocentesis? When is it performed?

Answer 12

Amniocentesis is a procedure in which amniotic fluid is removed from the uterus for testing or treatment. Carried out at around 17 weeks of pregnancy.

Question 13

What is chorionic villus sampling? When is it performed?

Answer 13

A test you may be offered during pregnancy to check if your baby has a health condition or chromosome condition. It involves removing and testing a small sample of cells from the placenta. Carried out at around 11 weeks.

Question 14

What is NIPD? When is it carried out?

Answer 14

New non-invasive method based on next-generation sequencing (NGS) of mothers blood. Can be used to identify whether a foetus has a single gene condition, such as cystic fibrosis or Huntington disease, by testing the foetal DNA in the mother’s blood. Carried out at around 10 weeks.

Question 15

How does NIPD work?

Answer 15

• Maternal serum contains placental DNA that matches the foetus genome - NGS genome sequencing is performed on the cell-free DNA

Question 16

What is NIPD also known as?

Answer 16

Cell free DNA screening

Question 17

Benefits of NIPD?

Answer 17

Results are far more accurate than current methods (>99% compared to 85% for Downs) and have a much lower false positive rate (0.06% compared to 5.4% for Downs)

Question 18

What does cell free DNA mean?

Answer 18

DNA is not in any cells, can just extract from blood sample

Question 19

What are potential dark sides to NIPD?

Answer 19

Since test introduced in Iceland, nearly no Down’s Syndrome babies are being born

Question 20

What is preimplantation diagnosis?

Answer 20

Refers specifically to when one or both genetic parents has a known genetic abnormality and testing is performed on an embryo to determine if it also carries a genetic abnormality. Would then only implant embryos without mutation.

Question 21

What is preimplantation diagnosis currently used for in UK?

Answer 21

HLA typing to match cord blood stem cells for siblings –> ‘saviour sibling’ Also used for single gene disorders Also used for non-disclosure testing (e.g. for Huntington’s disease)

Question 22

What is HLA typing?

Answer 22

HLA typing is a kind of genetic test used to identify certain individual variations in a person’s immune system. Critical for identifying who can safely donate bone marrow, cord blood, or an organ to a person who needs a transplant.

Question 23

What is non-disclosure testing?

Answer 23

Can perform screening of embryos without knowledge of disease status of parents

Question 24

How is non-disclosure testing used here?

• Woman has come to clinic
• Her mum died of Huntington’s
• She wants to make sure her baby does not get Huntington’s but does not want to know if she carries the gene herself

Answer 24

• Embryos with alleles ‘cc’ are discarded –> chance that one ‘c’ came from the grandma and potentially puts baby at risk of Huntington’s
  
  • Due to mum being ‘cd’
• Embryos with ‘cd’ are implanted –> ‘d’ allele must have come from mum therefore ‘c’ must come from dad (no Huntington’s)

Question 25

What is precision therapy?

Answer 25

A strategy that integrates molecular information with clinical data to select the best therapeutic intervention. Lots of different terminology used to describe the same thing * genetically-guided therapy * personalized medicine * stratified medicine

Question 26

What is gene therapy?

Answer 26

The use of genetic material (DNA or RNA) as a medicine * Introduction of functional genes, in the form of DNA, to replace mutated genes * Using gene technology to **repair mutated genes**, **silence overactive genes** and to also provide our immune cells with the tools they need to recognise and kill cancer cells and infections

Question 27

What is Leber's congenital amaurosis (LCA)?

Answer 27

* Rare inherited eye disorder that causes blindness at birth or infancy * Accounts for 10-18% of congenital blindness * Over 22 genes implicated * Recessive inheritance pattern

Question 28

Why is the eye ideal for gene therapy?

Answer 28

* Eye is immune privileged * Eye is accessible for subretinal injection

Question 29

What is gene editing?

Answer 29

A group of technologies that give scientists the ability to change an organism's DNA

Question 30

What is pharmacogenetics?

Answer 30

Correlation between the effect of drugs and the genetic constitution of patients

Question 31

Why is pharmacogenetics important?

Answer 31

* 100,000 deaths & 2 million serious adverse drug reactions each year in USA * 5-7% of hospital admissions due to adverse drug responses

Question 32

What are the cytochrome P450 enzymes? What are they responsible for?

Answer 32

* Multigene family of enzymes found predominantly in the liver * Responsible for the metabolic elimination of most drugs currently used (~75%) * Also important for converting pro-drugs to their active forms (eg codeine)

Question 33

What is CYP2D6?

Answer 33

A highly important **polymorphic** member of the cytochrome 450 family --\> metabolises 25% of drugs

Question 34

What are the potential results of the polymorphism of this enzyme?

Answer 34

Results in poor, intermediate, efficient or ultrarapid metabolisers (UMs) of CYP2D6 drugs. * 6-10% of Caucasians are non-metabolisers (no active CYP2D6) * 7% of Caucasians are ultra-rapid metabolisers (multiple copies of CYP2D6)

Question 35

What problems arise due to polymorphism of CYP2D6?

Answer 35

Same drugs will not work on everyone * Some won't be metabolised at all * Some will be metabolised too fast

Question 36

How is CYP2D6 involved in tamoxifen metabolism? How can polymorphisms affect this?

Answer 36

* CYP2D6 is the **rate limiting step** converting tamoxifen to its active metabolite **endoxifen** * Poor metabolizers due to CYP2D6 polymorphisms are associated with worse survival

Question 37

What is preventative medicine?

Answer 37

Information about a persons genotype or gene expression profile used to tailor medical care to prevent disease GP’s will have access to genotyping tests * prescribe depending on the results (eg CYP2D6) * change lifestyles to fit results

Question 38

Which embryos would be safe to implant?

Answer 38

ac, ad

Question 39

What are incidental findings?

Answer 39

Previously undiagnosed medical or psychiatric conditions that are discovered unintentionally and are unrelated to the current medical or psychiatric condition which is being treated

Question 40

How are incidental findings dealt with?

Answer 40

ACMG (American College of Medical Genetics and Genomics) guidelines --\> only report back on **actionable results** (called secondary findings) E.g. BRAC1 and long QT syndrome (cardiac defect leading to sudden death) Untreatable disorders, carrier status etc are **not fed back**