Rare diseases Flashcards
Why are rare diseases so hard to cure
- They are hard to diagnose – really hard to treat because really hard to diagnose
- Small population size
- Limited funding
Diagnosing rare disease
Rare disease = really hard to diagnose
- Really hard to treat rare disease because really hard to diagnose
- People = trained to find the most likely reason but rare disease might be the most likley trait = hard to diagnose
“When you hear hooves sometimes its a zebra” – rare because you think hooves (not always most common thing)
Mascot for rare disease
Zebra
Issue with Population size for rare diseases
- Harder to collect information
- Not enough cases/controls for GWAS study
Because of population size – hard to find what genes control it
- Can’t do GWAS to find what genes control it because there are few people = not enough to do GWAS
Funding for studying rare diseases
Federal grant monies are given to projects that will make the biggest impact
- Want to fund things that help the most people
- Hard to get people to help 1/2 families when can help 1000s = rare diseases get overlooked
Low profitability for corporations
- Companies won’t make money on drugs –> not enough people will buy it = companies won’t make it
Example Rare disease
Chronic Tubuliontersyitial Kidney Disease
Chronic Tubuliontersyitial Kidney Disease
Rare disease – A group of kidney diseases afefcteing tubules of kidney
- Chronic kidney disease
- Requires Dialysis
- Requires Kidney transplants
Rare – 500 US families
Answer: Autosomal Dominant
NOT X-linked because II.1 is affected if X linked = III.1 would have to be affected
Answer: 1 – because having one dominant allele is all you need to get the disease
If was controlled by two genes = you would need 2 dominant alleles –> would be in 1/16 kids
How can you identify the disease allele
- Sequencey entire genome
- Look at candidate genes
- Linkage
Why do we want to know the gene
If we know the gene = we can tailor treatment for disease
Issue with sequencing (Challeneges)
- Cost of sequencing (not as big of an issue now)
- Time and cost of sequence analysis –> we have the technology BUT need to anaylyze it
- Need to put small sequcnes together and compare it to others – takes time
- Accuracey – have a 99.99% accuracey BUT that would mean 300,000 inaccruacies when looking at 3 Billion BP genome
- If looking for one gene –> how will you find the one gene if it might have inaacuracies
Can do sequencing to find gene BUT it is not always productive
Using candidate genes Ex.
2018 – 500 US families had sequencing of candidate genes –> found mutations in different genes (MUC1, REN, SEC61A, UMOD1)
Looked at genes they knew were involved in kidney function
Using linkage to identify gene in rare disease
Don’t always need to find a gene mutation that causes disease –> can find something linked to the gene that has mutations
- Can see what SNP co-segragtes with disease THEN the SNP is a marker that is inherited with the disease
Most SNPs = not linked to gene just looking for ones that are
FINDING SNP = can show you region of the disease causing gene –> can then look for the gene more easily
- If use linkage – see SNP that is linked to the disease gene = know where to look for the disease gene
Answer: DA and dG –> If linked only get the parental gametes (same phase as parents) because no recombination
Answer: True –> unlinked means have Independent Assortment = get all 4 possible gametes
Gametic Phase
The allele combinations inherited from each parent
What does linkage lead to
Linkage leads to more parental phases in offspring
Example – AB/ab
AB and ab – parental (Non-recombinant) – if linked = they are more abundant
Ab and aB – Non-parental (recombinant) – require a recombination event
Answer: Parental (non-recombinant)
Maternal = need to be DA – because only can ge D from mom
- DA = parental
dA = paternal
Answer: Not possible to determine
DA = has to be maternal (can only get D from mom)
dA = paternal –> don’t know if recombinant or non-recombinant because can get dA with or without recombination
What do you need in order to know if something is parental or non-parental
Parents MUST be heterozygous at BOTH loci in order to deduce whether the offspring contains a parental or non-parental phase of alleles
Pedigree 1:
Mom = don’t know
Dad = don’t know
- Neither are heterozygous at both loci = can’t know
- Homozygous at one loci = can’t tell
Pedigree 2:
Mom = Parental
Dad = Don’t know
Pedigree 3:
Mom = Parental
Dad = Non-parental
- Don’t know which parent gave which gamete (could have been either giving them) BUT doesn’t matter (either way one is parental and one is non-parental)
First step in using linkage to find disease causing loci
Genotype each family member at markers all across the genome
Is the SNP linked to disease?
NOT LINKED
If linked = expect more parental than recombinant
Here:
2 Gametes parental
2 Gametes recombinant
(LOOK at ALL not just disease gametes)
Since equal recombinant and not recombinant = this SNP is NOT linked to disease causing allele – NOT linked to the Disease locus)
