Chromosomal Abnormalities Flashcards
What is metaphase?
- Chromosomes are condensed and can be karyotyped during metaphase
- Each chromosome comprises two chromatids at this point
- 4n prior to cell division
How is DNA compacted?
Chromatin
•Its not just about fitting a lot of DNA into the cell
•Proteins bound to the chromatin affect its regulation
•The 3D genome is important
What is G banded architecture?
Ideogram
•Chromosomes have some common structural features
•Giemsa staining leaves a recognizable pattern of bands
When is expression?
- Can be tissue specific
- Can be at a specific time in development
- Can be in response to an event
What is the purpose of mitosis?
- To create two identical daughter cells
- For growth and repair
- To replace exhausted cells
- 2n to 2n
How do you culture and harvest?
- 0.5ml blood in 5ml culture medium
- Add phytohemagglutinin (stimulates lymphocytes to divide)
- Culture 48-72 hours
- Add colecmins (arrests cells in metaphase)
- Culture breifly; add hypotonic KCl to swell cells; fix in 3:1 methanol: acetic acid; drop on to microscopic slide
- Brief digestion with trypsin stain with Giemsa
What is the purpose of meiosis?
- To achieve reduction from diploid (2n=46) to haploid (n=23)
- To ensure genetic variation in the gametes
- Enables random assortment of homologues and recombination
Why is there vulnerability of female meiosis?
- Paused in utero until puberty
- One primary oocyte yields only one ovum
- Finite number of primary oocytes
What is female non-disjunction?
•Most aneuploidy caused by non-disjunction arises in oogenesis
•Likely due to degradation of factors which hold homologous chromatids together
-Risk of maternal non-disjunction increases with age
-First trimester risk for trisomy 13,18 and 21
When does most trisomy 21 arise?
Maternal non-disjunction
What is Chromosomal aneuploidy?
Meiotic non-disjunction
•Trisomy for all chromosomes has been detected prenatally
•Not all trisomies are compatible with life
•Monosomy is poorly tolerated
Why is sex chromosome imbalance tolerated?
- X-inactivation of excess X chromosomes
* Low gene content of Y chromosome
What reciprocal chromosomal abnormalities have in common?
- Carriers (1 in 1000) are usually phenotypically normal
- Chromosomes have to contort into unusual figurations to achieve synapsis at mitosis and meiosis
- Present a reproductive risk: increased chance of unbalanced gametes
What are unbalanced chromosomal abnormalities?
- Severity of phenotype is dependent on gene content of affected segment
- Trisomy is usually more tolerated than monosomy
- May arise de novo or from a reciprocal parental abnormality
Describe Contiguous gene deletion syndromes:
The ‘phenotype first’ approach
- Clinical approach to grouping children with similar developmental delay and/or dysmorphism, then looking for common genetic abnormalities
- Yielded many ‘classical’ contiguous gene deletion syndromes
What are the symptoms of of Williams syndrome (7q11.23 deletion)?
- Long philtrum
- Short, upturned nose
- Arched eyebrows
- Supravalvular aortic stenosis
- Friendly, social ‘cocktail party’ personality – an absence of social anxiety
What are the phenotypes caused by in Williams syndrome (7q11.23 deletion)?
•Phenotypes caused by imbalance of genes which are unrelated apart from their genomic location
What are continuous gene deletion/ duplication syndromes?
- Have common breakpoints
- Mediated by low copy repeats (LCRs)
- Risk of NAHR may be increased by parental LCR inversions
What re the symptoms of 7q11.23 duplication syndrome?
•Delayed speech development
•Autistic behaviours that affect social interaction and communication
•Dilatation of the aorta
•Flat eyebrows
•Broad nose and short philtrum
Duplications usually have a milder phenotype than the reciprocal deletion
Describe genetic analysis
- Cost of genomic analysis greatly reduced
- Able to detect smaller imbalances
- Increased appetite for a genetic diagnosis
