Investigating Genetic Disorders Flashcards
What different types of reasons is genetic testing done for? (5)
Diagnostic Pre-symptomatic Carrier status Prenatal Risk factors
What was the largest activity of prenatal genetic testing for?
Common aneuploidies
What are the three common things testing for postnatally?
Cytogenetics in malignancy
Genetic risk factors
Molecular testing for rare single gene disorders
What are the two types of genetic testing?
Cytogenetic
Molecular
What conditions are most commonly (molecular) tested for postnatally? (5)
Fragile X Cystic fibrosis Breast cancer Haemochromatosis Factor V Leiden
What conditions are most commonly (cytogenetic) tested for postnatally? (2)
Solid tumours
Haematological malignancy
What conditions are most commonly (molecular) tested for prenatally? (3)
Sickle cell disease
Free fetal DNA - sex
Cystic fibrosis
What conditions are most commonly (cytogenetic) tested for prenatally? (2)
Karyotype
Aneuploidy
What is a genetic marker?
A marker tags a piece of DNA and can be used to track genes in families or populations.
What does SNP stand for?
Single nucleotide polymorphism
What is an STR?
Short tandem repeat (microsatellite), highly variable in length.
When is a genetic marker polymorphic?
When the frequency of the minor allele in the population is >1%
What different types of genetic conditions are there mentioned in this lecture?
Chromosomal abnormalities (e.g. Downs)
Single gene disorders (e.g. sickle cell, CF)
Cancer
Thrombophilia e.g. factor V Leiden
What does MAF stand for?
Minor allele frequency
What can be said about linked genetic markers?
They are physically close on the chromosome
Linked genetic markers mostly stay together through meiosis but can ….?
Cross over in recombination
What can linked genetic markers be used to track?
Location of a disease gene
What are the three different ways disease genes are identified?
Positional candidates
Functional candidates
Exome sequencing
How are positional candidates identified?
Genome wide genetic linkage analysis
How are functional candidates identified?
Functional association with previously identified disease genes
How are disease genes identified using exome sequencing?
The exome is sequenced and coding variants identified. Using exome sequencing controls and genetic variation databases, the common variants are excluded. This leaves the candidate genes only and so the disease genes can be identified.
What is the exome? How much of the genome does it make up?
All the protein coding regions of the genome.
~1.5%
What condition is given as an example in this lecture that the disease-causing gene was identified using exome sequencing? What is the gene?
Freeman-Sheldon syndrome (distal arthrogryposis)
MYH3 is the gene
How are genetic variants classified on a scale of 1 to 5?
- Non-pathogenic
- Unlikely pathogenic
- Variant of unknown Significance (VoUS)
- Likely pathogenic
- Pathogenic
How may searching medical literature be useful in classifying a genetic variant?
Can be decisive if there is a clear known precedent
How may searching databases be useful in classifying a genetic variant?
Can be decisive e.g. if there is a clear incompatible population frequency (too many people have the variant, can’t be disease causing).
When is using in-silico tools acceptable in classifying a genetic variant? When is it not acceptable?
To predict the severity of a variant
To rely solely on these predictions to assign pathogenicity to a previously unclassified variant.
