GENETICS - wk 2 Flashcards
retinoblastoma
- Commonest childhood eye tumour
- 1 in 15,000 children
- 3rd most common childhood cancer
- 18 mnths onset
- 60% present with leukonia – white pupil (in camera flash)
2 hit hypothesis in relation to retinoblastoma
- To explain hereditary retinoblastoma
- Discovered Because there are 2 groups of children getting it…
o Those getting it vv early on and both eyes affected
These children had a germline copy of the damaged gene present in all cells of the body, since only in one homolog it isn’t sufficient to cause disease, but a second hit leads to full blown disease
So their chances are greater than a non-carrier who would need to get ‘2 hits’ to get the cancer
o Those getting it when older only one eye affected
These children don’t have the germline copy
tumour supressor genes
- Control cell growth and differentiation
- Function as ‘cellular recessives’
- Follow the 2-hit hypothesis
o So both alleles for these genes must be affected for the phenotype to be negatively affected
You can inherit the first hit mutation autosomal dominantly
- But in any cell the second one must be faulty to cause cancer
genetic testing in complex genetic disorders - gene association studies
- More than one gene affected
- May not be genes may be regulatory
- Use Gene Association Studies
o Test many individuals with the gene you’re interested along with a control group of people that don’t have a specific gene
o If association between gene and disease or trait is present … a particular allele, genotype or haplotype of a polymorphism will be seen more often than expected by chance in an individual carrying the trait
testing for mendelian disease - what do we screen for
aka single gene disorders
POPULATION SCREENING - Neonatal screening for genetic mendelian disorders o Blood test (heel prick) at day 7 - Screened for… o Phenylketonuria Clinically silent in first months Eczema Hypopigmentation Severe developmental delay ‘mousey’ smell to urine o Congenital hypothyroidism o Cystic fibrosis o Medium chain acyl-CoA dehydrogenase deficiency o Sickle cell disorder o Hearing loss
what features make screening for a genetic disorder worth it
- well-defined disorder
- known incidence in a certain population
- significant morbidity or mortality
- effective treatment available
- period before onset during which intervention improves outcome
- ethical, safe, simple and robust screening test
- cost-effective
pre-symptomatic genetic testing
Does not necessarily require DNA test
- Clinical examination for discriminative phenotypes
- Investigation
- Family history changes prior risk
If done for medical reasons
- Should result in a preventative intervention
- Family implications need to be considered
Testing of children is appropriate if intervention starts in childhood
what are the 2 reasons for presymptomatic genetic testing and what are the pros and cons of the later
1- Medical reasons – to make sure interventions occur
2- Non-medical reasons – for adult-onset neurological disorders normally
- cons
o no medical benefit
o side-effect unknown (but inc. risk of suicide)
o many people request test to confirm they do not have the condition
o insurance/ mortgage problems
- pros
o removes uncertainty
o clarifies reproductive risk
o career/ lifestyle choices
what are the rules/issues for getting a non-medical presymp. genetic test
- performed only in specialist units
- restricted to adults
- obligate carriers are a problem (eg if child is positive then parent will know they are pos too)
- may be done for reproductive reasons
- should become rarer (due to better treatment in future)
de-novo mutation, distribution
- very common
- increase with paternal and maternal age
o both aged 20 1 in 377, both aged 45 1 in 168 - only affect genotype if the genetic change is in a functional area of the protein usually leading to loss of function
- severe but not as clinically distinctive
genomic imprinting definition and description
Differences in gene expression depending on whether a gene is maternally or paternally inherited
- specific chromosomal regions contain imprinted genes
- such regions usually contain both maternally and paternally imprinted genes
- normal cellular process
whats the significance of hemizygosity
means loss of one of the parents contributions/ alleles
- accounts for only a small number of genes expressed
- importance?
o Many developmental genes are imprinted
o Disruption of imprinting is implicated in several well-known genetic disorders and many cancers - Chromosome that was deleted in Angelman case was derived from mother
- In Prader-Willi case derived from father
- Loss of heterozygosity e.g. loss of one of the parents contribution
what are the 3 mechanisms behind loss of imprinting - and what is trisomic rescue
1- Chromosome deletion of maternal chromosome
2- Methylation abnormality
3- Uniparental disomy
o When both chromosomes are form the same parent as there would have been trisomy but the maternal chromosome has been kicked out via trisomic rescue
o Trisomic rescue is random so no guarantee it kicks out one of the extra paternal chromosomes
mitochondrial DNA
- only organelle with it’s own DNA
- 16.559 base pairs
- Many copies in a cell, dependant on energy requirement of cell/tissue
- Contains important genes for mitochondrial metabolism and ribosomal RNA
- Maternally inherited
- High rate of mutations
o Point mutations and deletions occur - Double stranded, ring structure, no introns
- Genes are tightly packed together
- Few or no non-coding nucleotides between genes
- Approx. 92% of mitochondrial genome has coding function
respiratory chain disorders what does it effect and how to diagnose
aka mitochondrial disease
- Disorder of high energy tissues
- Eg heart problems, brain problems, muscle problems, eye problems etc
Diagnose via
- Serum lactate > raised
- Mitochondrial DNA mutation > blood analysis
- Muscle biopsy
