chromosomal abnormalities Flashcards
- What is meant by karyotype?
An individual’s set of chromosomes in terms of number and structure of chromosomes
- How do you prepare a karyotype?
- Collect ~5ml heparinised venous blood
Can use amniotic cells, CVS- Isolate white cells
- Culture in presence of phytohaemagglutin
Stimulates T-lymphocyte growth/differentiation - After 48 hours add colchicine
Causes mitotic arrest - metaphase - Place in hypotonic saline
- Place on slide
- Fix and stain
- What is meant by chromatin?
- What stain is used to make a karytype?
A substance within a chromosome consisting of DNA and protein
Giemsa dye
- What are the 5 common structures, identified by the G-Banded architecture of a chromosome?
Telomere on either end of the chromosome
p-arm - short arm q-arm- long arm G-dark and G-light bands Centromere
- How would you refer to the small aberrations within chromosomes?
State whether they are on the p or q arm
State their band number (numbers go before letters) (based on position from centromere) State their sub-band number If possible state Sub-sub-band feature
- What does bphs stand for?
- What do the darker regions of a chromosome karyotype mean?
- What do the lighter regions of a chromosome karyotype mean?
Bands per haploid set
Dark = heterochromatin - more compact fewer genes Light = euchromatin - more open more genes
- Why are karyotypes performed more in Prophase rather than Metaphase?
- What is meant by Aneuploidy?
Because the chromosomes are less compact and therefore you get more detail from the karyotype
An abnormal number of chromosomes
- What is the purpose of meiosis?
- What method of genetic variation does meiosis enable?
To achieve reduction from diploid (2n = 46) to haploid (n = 23)
To ensure genetic variation in the gametes
Random assortment of homologues Recombination
- What is non-disjunction and what does it result in?
- If non-disjuncture occurs in meiosis I are all daughter cells affected?
- If non-disjuncture occurs in meiosis II are all daughter cells affected?
When chromosomes are not split properly between daughter cells
Always results in either 1+ (trisomy) or 1- (monosomy) chromosomes
Yes
No, half are affected
- What is the most common form of chromosomal abnormality?
- Why is sex imbalance tolerated?
Sex chromosome aneuploidy
X-inactivation of excess X chromosomes
Only 1 X chromosome activity
Low gene content of Y chromosome- so not much impact on phenotype
- Why, if inactivated, does abnormal number X have effect on phenotype?
Both X and Y chromosome have PAR (pseudo-autosomal region)
PAR still produces genes in this region
So when x chromosome is inactivated
genes in PAR region still active and can be transcribed (but autosomal function rather than sex chromosome)
- What is the second most common chromosomal abnormality in live births?
- What is this abnormality due to?
Trisomy 21 (Down Syndrome)
3 copies of chromosome 21 Non-disjunction during maternal meiosis (85-90%)
- What is correlation between maternal age and cases of trisomy per 1000 births?
- Why is it then, that 75% of children with Down syndrome are born to mothers under 35 (younger)?
As maternal age increases, the number of cases rises exponentially
Because 90% of children are born to mothers at this age
- Why does the increased maternal age and increased risk of trisomy correlation exist?
Older the mother, the longer the oocyte has been in the state of meiosis
So chromosomes do not line up as neatly during metaphase Likely due to degradation of factors which hold homologous chromatids together (cohesin)
premature separation of homologous chromosomes into separate sister chromatids
- Why does non-disjunction occur in the spermatogenesis?
Primary spermatocyte undergoes ~ 23 mitotic divisions per year and potentially accumulate defects
- What single gene disorders are parental age a risk factor of?
- What is the risk factor increasing chances of paternal involvement in aneuploidy?
Apert syndrome
Crouzon syndrome
Pfeiffer syndrome
Smoking
- What do the terms qter and pter refer to?
- What is ‘der’ an abbreviation of?
Tip of long arm
Tip of short arm Derivative chromosome (contains extra material)
- What are ‘ins’ and ‘inv’ abbreviations for?
- What is the abbreviation for translocation?
Insertion
Inversion t
- What does a +/- before a chromosome number, tell us about it?
- What does a +/- after chromosome number, tell us about it?
Gain/loss whole chromosome
Gain/Loss of part of a chromosome
- In what phase does the crossing over of chromosomes occur?
- What is the purpose of Crossing Over?
- How does Crossing Over occur?
Prophase I
To increase genetic diversity Pairs of chromosomes align Chiasma form Crossover occurs
- How often does Crossing Over occur?
- Explain how Unequal Crossing Over occurs?
1-3 times per chromosome per meiosis
Chromosomes do not align correctly at centromeres Unequal lengths of chromatids are exchanged Leading to deletion of genes in one chromosome And duplication of genes in the other chromosome
- What are the reasons for deletion of genes in single chromosome abnormalities?
- What is the most common cause for a duplication abnormality?
Unequal crossing over
Breaks in chromosome
Can occur at end
Most often caused by unequal crossing over
- What are the 2 types of inversion in single chromosome abnormalities?
Paracentric inversion - Breaks in chromosome occur in middle of chromosome arm & that section of chromosome is inverted, creating reinvented piece of DNA
Pericentric inversion - Breaks occur around centromere & that section of chromosome is inverted, creating reinvented piece of DNA
- Are carriers of inversion abnormalities affected?
Often carriers are not affected (as the same genes are present) , but can cause reproductive problems as children can have deletions and insertions
- Explain how the insertion occurs in 2-chromosome abnormalities
- what does this means for the patient
Section of chromosome from one chromosome is inserted into another chromosome
If translocation in balanced fashion, carrier is unaffected May cause problems in offspring if they inherit one normal and one translocated one- need to have either no translocated or both translocated to not be affected
- What is the theoretical % chance that the child of a parent with translocation of chromosomes will be affected?
50% as there is a 2 in 4 chance that there will be an unbalance
- What is meant by a Microscopic chromosomal deletion?
- What is meant by Chromosomal Microdeletion?
Deletion of chromosome can be detected easily in microscope
Cri-du-chat syndrome 46, XY, del(5p)
Deletion can be seen in high resolution banding Velocardiofacial/DiGeorge syndrome 22q11.2del but still 20+ genes deleted
- What is meant by a de-novo chromosomal abnormality?
- What causes William’s syndrome?
When the abnormality was not inherited from the parent of the patient and so it is new to the individual
7q11.23 deletion
- What are the symptoms of William’s syndrome?
Long philtrum
Slightly upturned nose Lack social anxiety Arched eyebrows Supravalvular aortic stenosis
- What are the phenotypes of William’s syndrome caused by?
- What is one of the chromosomal features of William’s syndrome?
Imbalance of genes which are unrelated apart from their genomic location
Lack of elastin on affected chromosome
- What are some of the symptoms of 7q11.23 duplication syndrome?
Delayed speech development
Autistic behaviours (social anxiety) Dilation of aorta Flat eyebrows Broad nose and short philtrum
- Compare the severity of the phenotypes of duplication and their corresponding deletion
Duplications usually have milder phenotype than the corresponding deletion
- Describe the 3 classes of chromosomes
Metacentric - Short arm p and long arm q (but relatively similar in length)
Submetacentric - short arm considerably shorter than long arm Acrocentric - short arm has been reduced to a short stump- non coding satellites
- Which chromosomes are generally acrocentric in humans?
- What type of translocation can only acrocentric chromosomes undergo?
- Can this type of translocation be homologous or non-homologous?
13, 14, 15, 21, 22
Robertsonian translocation Both
- Explain the mechanism behind Robertsonian translocation?
Both non coding satellites of the 2 different acrocentric chromosomes are removed
The remaining long arms join together - translocating to form a derivative chromosome
If this occurs during the development, most people are unaffected but why might their offspring still be affected?
no genetic information has been lost, just rearranged
but offspring may not inherit it in a balanced manner
- What are the 6 possible segregation products of the carrier that would be passed onto gamete for 21q14q?
14 & 21 - Normal
Derivative - Balanced
Derivative & 21 - Unbalanced (Down Syndrome)
21 - Unbalanced (lethal)
14 - Unbalanced (lethal)
Derivative & 14 - Unbalanced (lethal)
- What is meant by Mosaicism?
- By what 2 mechanisms can mosaicism occur?
Presence of 2 or more populations of cells with different genotypes
Non-disjuncture during early development Loss of extra chromosome in early development
- Are the results of the phenotypes of mosaicism generally mild or heavy?
- If everyone is thought to be mosaic, then why are most people not affected by it?
- What are the most common mosaics?
Mild
This mosaicism is lost in early development It will only become evident if passed on in germ cells Where one of the sex chromosomes has been lost during development 46XY/45X or 46XX/45X
