09 100K Genome Project Flashcards
Very common variants tend to have what effect?
Little effect
Very rare variants tend to have what effect?
Large effects and cause mendelian disease
What do you need to study the small effects of common variants?
Thousands of cases and controls for analysis
What type of cohort is good to study for severe mendelian conditions?
Small families with affected and unaffected people is fine, you can make comparisons within and between families
How many rare diseases are there?
7,000
As a rare disease definition, 1 in how many people are affected by a single rare disease?
1 in 2000
How many people in the UK have a rare disease?
3.5 million
What percentage of rare diseases are genetic?
80%
Every month how many new rare disease causes are found?
30
What are the symptoms of Burn McKeown Sdynrome (BMKS)?
Cleft palate, lower lid coloboma, hearing loss, prominent ears, thin upper lip, choanal atresia (blockage of nasal passage).
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?
It is likely to have a single genetic explanation
Where was a heterozygous variant found when pedigrees were made of a BMKS family?
A variant in TXNL4A, a spliceosome gene
WGS found the novel cause of BMKS, what was it?
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.
How much can 1 genome be to sequence now?
$100
What two groups of people were included in the 100K genome project?
Rare disease and cancer patients
What later step did the 100K genome project hope to include?
Infectious disease susceptibility
What was the cohort for the 2014 pilot of the 100K genome project?
3000 rare disease patients and 2000 cancer patients across 6 site in England.
Who did the 100K genome project?
NHS England and Genomics England (a government funded company)
What samples were taken from cancer patient in the 100K genome project?
A blood sample and a cancer sample
Could anyone get into the 100K genome project?
No, there were eligibility criteria. It needed to be specific types of cancer, and certain categories of rare disease.
What samples were taken from rare disease patients in the 100k genome project?
Blood samples, but trios if possible
WGS is used for childrens cancer like sarcomas in the NHS. But why is its use quite limited at the moment?
If it can’t inform cancer care then it isn’t valuable. it’s more valuable for rare disease patients.
What is a generic bit of eligibility for those joining the 100K genome project?
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.
Once someone’s eligibility was assessed for the 100k genome project, what happened?
They were invited to join, and informed consent was acquired.
What were some of the optional additional findings that you could opt in for the scientists to look for and tell you about?
Adult and child onset additional findings. Carrier testing. Parental carrier status for AR and X linked conditions.
What is a danger of all these additional findings?
You overburden the health service by finding out so much stuff, that may never happen, so many more tests are done.
Also false positives.
What’s the difference between incidental findings and additional findings?
Additional is when you are intentionally looking for it. Incidental is when just by chance you see an unrelated change.
True or False, Whole Genomes were looked at in the 100k genome project?
False, only the areas related to their conditions.
What was the diagnostic yield of the 100k genome project?
~25%
What advantage is there of WGS over WES?
splice site mutations and promoter region mutations can be identified
What successes have come out of the 100K genome project?
New diagnoses. Earlier treatment interventions for family members. Help give peace of mind to family members planning to have kids.
What was the cohort for the Bioresource WGS pilot study?
13,000 people, 10,000 of which had a rare condition.
What group have the highest diagnostic yield when WGS is done?
Children with retinal, neurological, and developmental difficulties.
What improves diagnostic yield?
Having trios/multiple cases
What are complex recessive cases?
Where a second, in trans, variant is identified
For what reason would it be good to pre-emptively snoop around in your genome and store it in hospital records?
For pharmacogenomics purposes. If you need to get a drug down the line, your data is then already there to predict what is best.
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?
Keep going back and reanalysing their data as new info becomes available. One day interrogate the non-coding genome more.
