09 100K Genome Project

Question 1

Very common variants tend to have what effect?

Answer 1

Little effect

Question 2

Very rare variants tend to have what effect?

Answer 2

Large effects and cause mendelian disease

Question 3

What do you need to study the small effects of common variants?

Answer 3

Thousands of cases and controls for analysis

Question 4

What type of cohort is good to study for severe mendelian conditions?

Answer 4

Small families with affected and unaffected people is fine, you can make comparisons within and between families

Question 5

How many rare diseases are there?

Answer 5

7,000

Question 6

As a rare disease definition, 1 in how many people are affected by a single rare disease?

Answer 6

1 in 2000

Question 7

How many people in the UK have a rare disease?

Answer 7

3.5 million

Question 8

What percentage of rare diseases are genetic?

Answer 8

80%

Question 9

Every month how many new rare disease causes are found?

Answer 9

30

Question 10

What are the symptoms of Burn McKeown Sdynrome (BMKS)?

Answer 10

Cleft palate, lower lid coloboma, hearing loss, prominent ears, thin upper lip, choanal atresia (blockage of nasal passage).

Question 11

If many characteristics of a patient fit together in a pattern we’ve seen before, what does that mean is likely about the genetic cause?

Answer 11

It is likely to have a single genetic explanation

Question 12

Where was a heterozygous variant found when pedigrees were made of a BMKS family?

Answer 12

A variant in TXNL4A, a spliceosome gene

Question 13

WGS found the novel cause of BMKS, what was it?

Answer 13

A small bit of the promoter missing in all individuals. This GC region in the promoter to exon 1 region needed WGS to look at it.

Question 14

How much can 1 genome be to sequence now?

Answer 14

$100

Question 15

What two groups of people were included in the 100K genome project?

Answer 15

Rare disease and cancer patients

Question 16

What later step did the 100K genome project hope to include?

Answer 16

Infectious disease susceptibility

Question 17

What was the cohort for the 2014 pilot of the 100K genome project?

Answer 17

3000 rare disease patients and 2000 cancer patients across 6 site in England.

Question 18

Who did the 100K genome project?

Answer 18

NHS England and Genomics England (a government funded company)

Question 19

What samples were taken from cancer patient in the 100K genome project?

Answer 19

A blood sample and a cancer sample

Question 19

Could anyone get into the 100K genome project?

Answer 19

No, there were eligibility criteria. It needed to be specific types of cancer, and certain categories of rare disease.

Question 20

What samples were taken from rare disease patients in the 100k genome project?

Answer 20

Blood samples, but trios if possible

Question 21

WGS is used for childrens cancer like sarcomas in the NHS. But why is its use quite limited at the moment?

Answer 21

If it can’t inform cancer care then it isn’t valuable. it’s more valuable for rare disease patients.

Question 22

What is a generic bit of eligibility for those joining the 100K genome project?

Answer 22

If you had had the other tests available at the time and nothing was found, then you were eligible. Otherwise it would have been a poor use of resources.

Question 23

Once someone’s eligibility was assessed for the 100k genome project, what happened?

Answer 23

They were invited to join, and informed consent was acquired.

Question 24

What were some of the optional additional findings that you could opt in for the scientists to look for and tell you about?

Answer 24

Adult and child onset additional findings. Carrier testing. Parental carrier status for AR and X linked conditions.

Question 25

What is a danger of all these additional findings?

Answer 25

You overburden the health service by finding out so much stuff, that may never happen, so many more tests are done. Also false positives.

Question 26

What's the difference between incidental findings and additional findings?

Answer 26

Additional is when you are intentionally looking for it. Incidental is when just by chance you see an unrelated change.

Question 27

True or False, Whole Genomes were looked at in the 100k genome project?

Answer 27

False, only the areas related to their conditions.

Question 28

What was the diagnostic yield of the 100k genome project?

Answer 28

~25%

Question 29

What advantage is there of WGS over WES?

Answer 29

splice site mutations and promoter region mutations can be identified

Question 30

What successes have come out of the 100K genome project?

Answer 30

New diagnoses. Earlier treatment interventions for family members. Help give peace of mind to family members planning to have kids.

Question 31

What was the cohort for the Bioresource WGS pilot study?

Answer 31

13,000 people, 10,000 of which had a rare condition.

Question 32

What group have the highest diagnostic yield when WGS is done?

Answer 32

Children with retinal, neurological, and developmental difficulties.

Question 33

What improves diagnostic yield?

Answer 33

Having trios/multiple cases

Question 34

What are complex recessive cases?

Answer 34

Where a second, in trans, variant is identified

Question 35

For what reason would it be good to pre-emptively snoop around in your genome and store it in hospital records?

Answer 35

For pharmacogenomics purposes. If you need to get a drug down the line, your data is then already there to predict what is best.

Question 36

60-65% of people who took part in the Bioresource WGS pilot study don't have an answer yet for their condition, what do we need to do?

Answer 36

Keep going back and reanalysing their data as new info becomes available. One day interrogate the non-coding genome more.