Intro to genetic testing Flashcards
What are the three categories of DNA diagnostic testing?
1) infectious disease testing (e.g. HIV, hep B)- biggest
2) Cancer genetics
3) Molecular genetics
is medical management directive or non-directive?
Directive. This is predictive molecular genetic testing WITH treatment. Personal decision making is predictive withOUT a treatment in mind (carrier screening)-i.e. for something like huntingtons disease where you can’t do anything about or for assessing pregnancy risks, etc. These are both uses of molecular testing.
How does Linkage analysis work?
(common in 1980s) This is an INdirect test. Ex. You know a disease is present but can’t find it on a gene and don’t know what the mutation is. In looking at a gene in someone who is affected and someone who is not, you can predict (with relative certainty- not total) whether a fetus is at risk. It will not tell you what the mutation is*, but based on surrounding polymorphisms, you can predict the likelihood of passing it on. Not common anymore and only useful if you are certain about the diagnosis and the gene involved.
What are the common mechanisms for mutation for CF and BRCA 1 gene?
roughly 85-90% in both are point mutations and 10-15% are the result of large deletions
both have low new mutation rates (most mutations already exist in families)
CF-autosomal recessive (on chromosome 7) uses a targeted approach because almost 90% of mutations are caused by the same known mutation (high carrier frequency)
BRCA (autosomal dominant) has high mutation frequency, mutation panels only used in special populations (Ashkenazi Jews), general scanning more common
What are the major causes of Duchenne muscular dystrophy?
(x-linked) 75% large deletions and 25% point mutations; high de novo mutation rate (so targeted approaches aren’t very effective); allelic heterogeneity; 1/3 of men with no family history (simplex) will be new mutation
What are the major causes of Huntington disease?
TNR expansion
What is the basis of targeting testing?
looking for one or more specific mutated (or susceptible) genes. Can look for mutations as small as 1 bp
can look for:
- single mutation types (factor V leiden)
- mutation panels (in a single gene- think CF)
- gene panels
targeted mutation panels are common in CF (23 mutations is the minimum and test will detect about 85% of mutations- will miss 15%) and in Tay-Sachs (will catch about 98%) and
gene PANELS are common in BRCA testing
What are the major strengths of targeted testing?
very high accuracy for specific alleles being assayed, widely available, affordable
What are the major weaknesses of targeted testing?
no information about other potential variants other than what’s on the test panel (in that gene OR in other genes)
What is the basis of gene scanning?
a discovery approach. typically follows unsuccessful target testing, and screens a gene (or multiple) to find any point mutation from a consensus sequence of a normal gene (so, for example, in CF this will find the other 15% of mutations). Exons, promoters, splice regions, any intron regions where mutations are known to be found are sequenced but introns are not typically sequenced so you won’t find EVERY mutation (thus it is 98-99% accurate, not 100%)
Useful in disorders where there is extensive allelic heterogeneity and where families are likely to carry “private” mutations
What are the possible outcomes of gene scanning?
positive result- pathogenic mutation detected
negative result- nothing found
variant of uncertain significance (VUS) - mutation that hasn’t been reported before and is hard to interpret (CANNOT make clinical decisions based on this)- presumed not to be pathogenic/clinically significant initially
many benign variants are expected
What are the strengths of gene scanning?
comprehensive; once mutation is identified, other family members can be screened using targeted screening
What are the weaknesses of gene scanning?
not all mutations will be detected; interpretations can be difficult and can be difficult on patients when inconclusive results are found; polymorphisms are expected
What is the ‘ACCE’ framework for genetic testing?
Analytic validity- accuracy of test
Clinical validity- ability of test to predict outcome
Clinical utility (most important)- ability of results to be used constructively for the patient/ improve outcome
Ethical, social, and legal issues
How is autism genetically tested?
large gene (30-100 genes) panels
