Investigating a Genetic disorder in childhood Flashcards
What is the role of a clinical geneticist?
- Diagnosis of genetic disorders
- Investigation and genetic risk assessment
- Genetic counselling
- Appropriate follow-up support to patient and extended family
- Liaison with genetic laboratories
- Education and training
- Research
Name some genetic conditions that you can get
- chromosomal abnormalities
- cancer
- thrombophilia
- single gene disorders
Name an disease example of chromosomal abnormalities
down syndrome
what can increase you risk of thrombophilia
- factor V linden can increase the risk of thrombophillia by 5 times
Downs syndrome is a ..
aneuploid disease
describe what is screened in prenatal testing for genetics
The largest activity (>80%) is screening for the common aneuploidies (Downs syndrome)
Specific testing for a large number of rare single gene disorders
What does aneuploid mean?
Aneuploidies –anything that is not 2 (diploid) e.g. trisomies
What does postnatal genetic testing involve
- Cytogenetics (take cells from the idnivdiual and look at the shape and size of the chromosomes) in malignancy
- Gene panels, screening for suspected single gene disorders – set genes based around a phenotype – rule
- Genetic risk factors – get an idea about what the genetic makeup is, in terms of common genetic risk factors that predispose you to some condition
What is a genetic marker
• a marker tags a piece of DNA and can be used to track genes in families or populations
name two examples of genetic marker
SNP = single nucleotide polymorphism STR = short tandem repeat (these are variable in length)
What does polymorphism mean
• they are polymorphic when the frequency of the minor allele in the population is >1%.
What is the minor allele frequency
this is the percentage of the gene in the population
Describe what a single nucleotide polymphorms is
- these are changes in one gene that happen in a population, for example someone could have either a C or a T, therefore they can have 3 types of allele either CC, CT, or TT.
what are short term tandem repeats
Short tandem repeats (STRs) are regions of the human genome that vary in length between people based on a repeated DNA sequence that repeats itself in the DNA
what is an allele
This is a different version of the same gene
what does linkage mean
- Linkage = means physical proximity, genetic markers can be close to each other
What is genetic markers in linkage analysis about
- idea that linked markers are physically close and are called a haplotype
- these markers stay together during meiotic recombination and can cross over in recombination
- they can be used to tract a location of a disease in gene in families
name the three ways how you can identify disease genes
- positional candidates
- functional candidates
- exome/genome sequencing
How is positional candidates identified
• Identified through genome wide genetic linkage analysis.
How are functional candidates identified
Identified by a functional association with previously identified disease genes
How are genome/exome sequencing identified
Identified as having rare variants in multiple unrelated affected individuals – an allelic series
- for example you remove all the common variants and this leaves the candidates genes
- you then get multiple people with the same condition and compare the cases to see which genes are shared between the individuals
- eventually you end up with on candidate gene that causes the condition
What is an exome
the protein coding regions of the genome
What percentage does the exome make up of the genome
- Makes up 1.5% of the genome
How do you know if a genetic variant is causing a disease
- Benign
- Likely benign
- Variant of unknown significance (VUS)
a. Don’t know what to do. - Likely pathogenic
- Pathogenic.
Name three ways in which you can approach hairnet classification
Searching medical literature
- Can be decisive, clear known precedent
Searching population databases
- Can be decisive, clear incompatible population frequency
- Genome Aggregation Database (gnomAD)
Using in-silico tools
- Acceptable to predict the severity of a variant
- Unacceptable to rely solely on these predictions to assign pathogenicity to a previously unclassified variant.
describe examples of
- benign
- supporting evidence
- moderate evidence
- definitive disease cause
= Minor allele frequency is too high for disorder OR observation in controls inconsistent with disease penetrance = benign
= Multiple lines of computational evidence support a deleterious effect on the gene /gene product = supporting evidence
= De novo (without paternity & maternity confirmed) – in the child but no in the parents so this is moderate evidence of support
= Prevalence in affected statistically increased over controls = comes up in variant but never in controls so definite disease cause
What is the impact of a genetic disease on the family
• diagnosis:
- confirmation, clarification
- pre-symptomatic, monitoring, search for donor
- pattern of inheritance, carrier testing
- prenatal, preimplantation, genetic counselling
What is the treatment of a genetic disease
- tailor treatment: appropriate drugs
- storing cells
- rational drug design
- gene therapy
