Chromosomal Abnormalities Flashcards
How do you prepare the karyotype
Collect 5 ml heparinised venous blood ( can use amniotic cells, CVS)
Isolate white cells
Culture in presence of phytohaemagglutinin ( stimulates the T lymphocyte growth/differentiation)
After 48 hrs add colchicine - causes mitosis arrest - metaphase
Place in hypotonic saline
Place on slide
Fix and stain with gisema
DNA compaction
DNA is condensed into chromatin which is wrapped around his tones. Proteins bound to chromatin affect its regulation and the 3D genome is important.
What is the short arm called
P arm
What is the long arm of the chromosome
Q arm
What is a telomere
The caps at the end of the chromosome
Why are the bands different colours
Some areas take up more gisema and appear dark while some areas take up less gisema and appear light
Regions of different compaction
Dark ( heteronormative) more compact fewer genes
Light ( euchromatin ) more open more genes
What does bphs mean
Bands per haploid set
What is karyotype
Chromosome count of individual - can detect major chromosome abnormalities
When is karyotyping done
Usually metaphase but also prophase as the chromosomes are less compact and therefore you get more detail from the karyotype
Aneuploidy
Abnormal number of chromosomes .you can cope with a missing number of genes but if the chromosomes are missing, the a whole number of genes are affected which causes problems and results in syndromes
Chromosome non disjunction
Non disjuncture results in uneven numbers of
Chromosomes in daughter cells .
Can occur in meiosis 1 or 2 .
Meiosis 1 all daughter cells affected
Meiosis 2 , half of daughter cells affected
When fertilised, either trisonomy or monosomy
Sex chromosome aneuploidy
Most common form of chromosomal abnormality . Affects more males
Why is sex chromosome imbalance tolderated
X inactivation of excess X chromosomes , only one X chromosome active. Low gene content of Y chromosome
PAr
Pseudo autosomal region
Does the risk of maternal non disjunction increase with age
Yes
Why is there a maternal age effect
Vulnerability of oogenesis ( differentiation of ovum)
Paused in Utero in prophase I until puberty
Secondary oocyte arrests in metaphase II
Only competes if fertilised
One primary oocyte yields only one ovum
Finite number of primary oocyte
Female non disjunction
Most aneuploidy caused by non disjunction arises in oogenesis
Likely due to degradation of factors which hold homologous chromatids together during metaphase
Paternal age effect - spermatogenesis
Vulnerability of male meiosis
Primary spermatocytes undergo approx 23 mitotic divisions per year and potentially accumulate defects
Paternal age effect
Paternal age effect affects a subset of single gene disorders caused by point mutations in FGR2 , FgR3 and RET
Eg. Apert syndrome
Crouzon syndrome
Pfeiffer syndrome
Trisomy vs monosomy
Most trisomies are not compatible with life and monosomy is very poorly tolerated
Crossing over of chromosomes
Occurs in prophase 1 Increases genetic diversity Pairs of chromosomes align Chiasma form and crossover occurs 1-3 times per chromosome per meiosis But can go wrong
Single chromosome abnormalities
Deletions; Can be the result of unequal cross over
Breaks in chromosome
Can occur at ends
Duplication; most often caused by unequal cross over
Paracentric inversions:
Can cause reproductive problems
Children’s with deletions / insertions
Two chromosome abnormalities
Insertions and translocation
If balanced does not affect carrier but may cause problems in off spring
Can cause partial trisomy or monosomy ( cri- du chat syndrome )
Can occur in somatic cells , cf, Philadelphia chromosome, cmL
Chromosomal deletions
Can either be microscopic or micro deletion microscopic criminal deletions can be easily detected in microscopes . micro deletions are were 20+ genes can be deleted
Eg cri du chat syndrome
Williams syndrome
Deletion
Long philtrum Short upturned nose Arched eyebrows Suprvalvular aortic stenosis Friendly social personality and absence of social anxiety
Phenotypes caused by imbalance of genes which are unrelated apart from their genomic location
How can Williams syndrome be detected
Deletion is too small to detec5 using standard karyotyping
Can be detected using targeted FISH
Fluorescent in situ hybridisation - lack of elastin on affected chromosome
Difference between 7q11.23 deleti9n ( Williams ) and duplication syndrome
Duplication;
Delayed speech development
Autistic behaviours that affect social interaction and communication
Dilation if the aorta
Flat eyebrows
Broad nose and short philtrum
Duplications usually have a milder phenotype than the reciprocal deletion
Classes of chromosomes
Meta centric; short arm and long arm are equal lengths
Submetacentric; short arm is a lot shorter than the long arm
Acrocentric: short arm has been reduced down to a vestigial stump
What is a robertsonian translocation
Occurs between acrocentric chromosomes
Most common 13 and 14, 14 and 15 , 14 and 21
Whilst silent in carriers, it can produce affected offspring
Mosaicism
Presence of two or more populations of cell with diff genotypes
X inactivation results in mosaic expression
Mosaicism can arise two mechanism;
- non disjuncture during early development
- loss of extra chromosome in early development
Results in Generally milder phenotype
- some lethal aneuploidy survivable if mosaic
Most common mosaic 46,XX /45,X, mosaic 46,day/45,X
