Download Variant prioritization in NGS studies: Candidate gene prioritization

Variant prioritization in NGS studies:
Candidate gene prioritization
(Practical) "
Work through the following practical exercises on your own."
"
The objective of these exercises is to become familiar with the
concepts of variant and candidate gene prioritization."
CANDIDATE GENE
PRIORITIZATION"
We will now look at prioritizing your list of interesting variants
further. As a biologist, what would the next logical question be?"
"
•  Ordinarily you would extract the list of gene symbols from this
file and examine all of them for possible links to the disease of
interest."
"
•  For this example, use the following list of genes from your
interesting variants file & pick one or two others that you think
are good candidates:"
•  MYO5C; CYP2C9; TTN; F5; CCDC141!
CANDIDATE GENE
PRIORITIZATION"
For each of these “candidate” genes:"
•  Use OMIM to get a broad idea of their function & what
diseases they might be involved in (if any)"
•  Use Phenolyzer to see what phenotypes are associated with
mouse/rat knockout models?"
•  Use BioGPS to see which human tissues these genes are
expressed in?"
•  Use KEGG to see if these genes are involved in any pathways
which may be linked to our disease features?"
Now, do you have any very strong candidates related to your
disease?"
VARIANT PRIORITIZATION"
Go back to your file of interesting variants and find the variant/s
from your strong candidate gene."
(If you didn’t find any strong candidates, have a close look at the F5 gene!)"
"
•  Is it a known SNP? (does it have a dbSNP rsID?)"
•  Use SNPedia to look for any known phenotypes associated with
this variant."
•  Is the “correct” allele seen in our patient? i.e. is it concordant
with the phenotype?"
•  Does the text highlight any allele-allele or gene-gene interactions
that might be of interest? If so, go back to your unfiltered
annotated .vcf to see if they might be present"
PHARMACOGENOMICS"
So by now you know your patient has the factor V Leiden mutation
which is strongly associated with Thrombosis. Typically, treatment
for Thrombosis involves the prescription of blood thinners such as
Warfarin. As a clinician you are aware of PGx associations with
Warfarin metabolism so you want to see if your patient has any of
the associated variants."
"
•  Go to PharmGKB and search for “Warfarin”"
PHARMACOGENOMICS"
The clinical PGx tab highlights 3
variants that influence Warfarin
metabolism"
•  What are they?"
Click through to Clinical Annotations
and examine the level of evidence for
these associations."
•  Is there enough evidence to
recommend adjusted dosing
guidelines?"
PHARMACOGENOMICS"
Go back to your original unfiltered, annotated .vcf file to see if
any of these variants are present."
"
•  Why would you check the unfiltered file rather than your
filtered file of interesting variants?"
"
•  In conjunction with the information provided by PharmGKB,
would you adjust your patients Warfarin dosage
prescriptions?"