Direct to Consumer Genetic Testing

Question 1

what is genetic testing?

Answer 1

Genetic testing is determining which variant or variants a person has in their genome and giving advice on the basis of what the current state of knowledge is about those variants.

These could be single gene, gene panel or genomewide tests

Question 2

what is genetic testing useful for?

Answer 2

diagnosing disease
pinpointing genetic factors causing disease
predict how severe disease might be
choose best medicine and correct dose
disocver genetic factors that could be passed down
screen newborns for treatable conditions

Question 3

what are single gene tests and examples?

Answer 3

looks for disorders caused by a single gene.

eg: Haemoglobin for haemoglobinopathies
Many enzymes for metabolic disease
CFTR for cystic fibrosis
BRCA1/BRCA2 for breast cancer
HTT for Huntington’s Disease

Question 4

what are gene panels and example of what its used for?

Answer 4

Gene panel testing is now carried out using NGS to screen for variants in 10s-100s of genes

commonly used in cancer

Question 5

what is a genomewide test?

Answer 5

microarray based: SNPs, CNV

Next gen seq: Exome, whole genome

Question 6

NGS in DTC

Answer 6

very new, three companies do exome sequencing: 23 and me, gene by gene and mapmygenome

5 companies do whole genome seq: full genomes corp, guardiome, gene by gene, sure genomic and veritas genetics

Question 7

examples of clinical uses?

Answer 7

Rare Disease – Cystic Fibrosis

Cancer Risk – BRCA1/BRCA2

Genetic Risk – Alzheimer’s Disease

Drug Response – Warfarin

Question 8

rare diseases and genetic testing

Answer 8

23andMe screen for 43 rare diseases, such as
Cystic Fibrosis
Hereditary Hearing Loss
Sickle Cell Anaemia

These are called carrier tests as the disease is likely to be evident in people who are homozygous for disease-causing variants

Useful for family planning

Question 9

what is CF?

Answer 9

Characterised by thick viscous mucus, particularly in the lungs

This leads to regular infections and long-term degradation of lung function

CF symptoms can also include loss of pancreas function and infertility in men due to absence of the vas deferens

Question 10

pathophysiology of CF?

Answer 10

Gene discovered in 1989

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) -mutated

CFTR regulates the flow of Chloride ions in and out of cells in the mucosal epithelium

Question 11

treatments of CF?

Answer 11

physio
DNAse
hypertonic saline
bronchodilators
antibiotics
special diet.enzymes/vitamins
lung transplant

Question 12

what is ivacaftor?

Answer 12

drug used to treat cystic fibrosis in people with certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene

CF patients with the G551D mutation (4% of cases)

Question 13

how does ivacaftor work?

Answer 13

Ivacaftor prolongs channel opening, increasing chloride ion movement to more normal levels

Question 14

how do lumacaftor and ivacftor work together?

Answer 14

used in CF patients with Phe508del mutation (70%)-CFTR misfolds and is degraded

Lumacaftor acts as a chaperone, ensuring more correctly folded CFTR reaches the membrane. Ivacaftor is needed to improve the channel function

Question 15

how does ataluren work?

Answer 15

used in CF patients with premature stop codons (5-10%)

Nonsense-mediated decay of mRNA

Ataluren makes ribosomes less sensitive to premature stop codons by allowing them to incorporate near-cognate tRNA, for example Trp, Arg, or Cys instead of UGA

Question 16

genetic testing and cancer risk?

Answer 16

BRCA1 and BRCA2 genes encode tumour suppressor proteins (DNA repair enzymes)

12% of all women develop breast cancer at some time
1.3% develop ovarian cancer

Specific mutations in the BRCA1/BRCA2 genes increase the lifetime risk of breast and ovarian cancer
4-5x increased risk of breast
30x increased risk of ovarian

They only account for 5-10% of all breast cancer and 15% of ovarian cancer

Question 17

how many isoforms of apolipoprotein E (ApoE and where do they differ)?

Answer 17

3, ApoE2, ApoE3, ApoE4

– differ at positions 112 and 158

Question 18

What is ApoE?

Answer 18

Cys112Arg and associated with atherosclerosis and Alzheimer’s Disease (AD)

Question 19

E4/E4 homozygotes are?

Answer 19

10-30x more likely to develop AD than E3/E3

Question 20

what is warfarin?

Answer 20

Anticoagulant

Prescribed for stroke, heart attack, deep vein thrombosis and pulmonary embolism

Coagulation time has to be monitored closely to avoid failure to clot

Interacts with NSAIDs, alcohol and foods high in vitamin K

Different genotypes have different responses

Question 21

what is CYP2C9?

Answer 21

Warfarin is mainly metabolised by oxidation in the liver by cytochrome P450 2C9

Encoded by CYP2C9 gene
Two known SNPs in CYP2C9

Wild-type allele

SNP1-reduces warfarin metabolism by 30%

SNP2-reduces warfarin metabolism by 90%

Question 22

what is VKORC1?

Answer 22

Warfarin works by inhibiting the vitamin K epoxide reductase complex, subunit 1 (VKORC1)

One SNP in VKORC1 gene -1639 G->A

Carriers of the A allele produce less VKORC1 and so need less warfarin to achieve same effect

Question 23

non clinical exampls of DTC?

Answer 23

paternity, ancestry, nonclinical traits

Question 24

how does genetic testing tell us about ancestry?

Answer 24

Uses known markers in the Y-chromosome (male), mitochondrial genome (female) or autosomes

Estimates how similar your markers are to marker sets in known ethnic groups and hence derive genetic relationships

Question 25

what types of non-clinical traits can be found?

Answer 25

eye colour - HERC2
red hair - MC1R
bitter taste perception - TAS2R38
earwax type - ABCC11
lactose intolerance - LCT
Alcohol flush reaction - ALDH2

Question 26

how is genetic testing used on animals?

Answer 26

Animals are also the focus of direct to consumer genetic testing

Breed identification and inherited diseases are the main areas

Livestock are also intensively tested for breeding

Question 27

positives of DTC genetic testing

Answer 27

Patient Choice/Right/Empowerment

Not on patient medical record

Identify variants that may increase disease risk
Planning for the future
Lifestyle changes
Enhance involvement in treatment

Information regularly updated
Identify carrier status for family planning
Paternity tests can be very helpful

Question 28

negatives of DTC genetic testing?

Answer 28

Incidental Findings
Radical lifestyle changes may follow
No treatment for many diseases
Your results may affect others in the family
Environment is very important in many common disease risk variants
Literature changes all the time
Consumer protection

Question 29

clincal concerns?

Answer 29

“Dr Google”
Lack of genetic counselling
Patient ability to understand results
Increases patient anxiety

Questionable clinical utility
Not able to answer patient questions
Advertising/Bias for drug companies

Question 30

genetic testing and cancer risk?

Answer 30

BRCA1 and BRCA2 genes encode tumour suppressor proteins (DNA repair enzymes)

12% of all women develop breast cancer at some time
1.3% develop ovarian cancer