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
whats the inheritance pattern of mitochondrial disease
- Similar to x-linked
- No male-to-male transmission
- Maternal inheritance only if affected gene is from mitochondrial DNA
- Mitochondrial DNA does not code for all mitochondrial protein
- If mitochondrial protein is coded from genomic DNA then follows a mandelian pattern of inheritance
what are some possible phenotypes of mitochondrial mutations
- Pearson syndrome
- kearns sayre syndrome
- myopathy
- ataxia
- cardiomyopathy’s
- leighs encephalopathy
heteoplasmy definition and 2 different mechanisms
Different daughter cells contain different proportions of mutant mitochondria
Can happen at 2 levels
- At the oocyte when cells are dividing
o So, different daughter cells have different distributions of the mutated DNA
- Or at tissue level
o So when cell is dividing if the mutated DNA contributes to high energy tissues then will be more highly affected than if it contribute to different tissues
triplet repeat expansions description and other name for it
Another name for these is DYNAMIC MUTATIONS
- This is because these mutations are still evolving through generations
- Not stably inherited
- Mutations are (usually) increasing in size with successive generations
- Has a threshold effect
- Exhibit a relationship between severity and copy number
o Explains phenomenon of anticipation (more severe in succeeding generations)
state the gender bias of triplet repeat expansions in 2 disorders
- Expansions of repeats usually has gender bias
o Eg. HD expansion when transmitted from paternal line
o Fragile X – expansion transmitted from maternal line - Accounts for over 40 neurological, neuromuscular and neurodegenerative disorders
myotonic dystrophy explanation and genetic underpinning
- Emotionless faces
- They can’t shake your hands
- CTG trinucleotide repeat in 3’ UTR of myotonic dystrophy gene
- Normally 5-27 copies of repeat
- Disease alleles 50-2000 repeats
- Repeat expands in males or female transmission
o But sudden increase in repeats from maternal transmission - Disease shows anticipation
digenic inheritance
- First came to light with sensorineural deafness
- > 100 genes involved
- Usually conforms to mendelian patterns of inheritance
- However, a proportion of proportion of patients with deafness, were double heterozygotes for known deafness genes
o Ie no hearing deficit were found in patients who were only carriers of a mutation in a single locus but deafness occurred where patients were carriers of mutations in 2 gene loci
contiguous gene deletion syndrome definition
A syndrome caused by a microdeletion that spans two or more genes along a chromosome
subtelomeric chromosomal rearrangements - why telomeres?
Why focus on telomeres?
- Majority of translocations involve chromosome ends (shared telomere-associated repeats)
- Gene rich adjacent regions (rearrangements likely to have phenotypic consequences)
Moderate-severe MR
- For sporadic cases (7%)
- For familial cases (25%)
mosaicism definition and 2 variations
When an individual is made up of populations of cells with different genetic constitutions
Can be mosaic for…
- Chromosomal aneuploidy
- Molecular mutations
somatic mosaicism in the average person
All cells suffer mutations as they divide
- At meiosis and at mitosis
- Approximately 10^6 per gene per cell divisions
Given the numbers of cell sin the body
- Everybody will have some cells which has a mutation of some sort
Repair Mechanisms Exist
- Can give rise to reversion
pathological mosaicism - when it becomes clinically important and signs of it in patients
May become clinically important…
- If mutant cells have tendency to grow and replace normal cells (cancer cells)
- If the mutation arose early in embryonic development, so becomes a large proportion of the whole body
- If the mutation occurred in the germ line
Signs of mosaicism…
- Differential growth patterns eg one leg more than another
- Mutations in the skin
- Some conditions only exist as a mosaic if the pure line is lethal – trisomy 14, tetrasomy 12
gonadal mosaicism - common in what diseases and what does it lead to in terms of testing
- Commoner in some diseases
o Duchenne muscular dystrophy
o Osteogenesis imperfecta - Can offer pre-natal diagnosis for a second child, even when parents are unaffected
- Causes recurrence risk for fatal dominant conditions
