Structural Chromosome Abnormalities Flashcards
(38 cards)
Name some types of rearrangements.
Translocation (reciprocal, insertional, robertsonian) Inversion (peri or paracentric) Deletion Duplication Isochromsome Marker
What is the most common recurrent rearrangement known to man?
What are the 2 others?
t(11;22)(q23.3;q11.2) is most common
t(4;8) and t(X:Y)
Approximately what number of liveborn individuals carry a balanced translocation?
1 in 500
What is a robertsonian?
Fusion of 2 acrocentric chromosomes. Usually non-homologous.
What is the most common robertsonian? Why?
The der(13;14) and the der(14;21) are the most common (the 13;14 accounts for ~75% of all rob translocations).
The sequence on 14p is very similar to both 14 and 21, but the sequence is in opposite orientation. This is what underlies the formation of the rob.
How is a robersonian formed?
Fusion of 2 acrocentric chromosomes - usually non-homologous.
Break occurs in both short arms of acrocentric’s and a dicentric robersonian is formed. One centromere is commonly suppressed and is not visible by cyto.
Approximately what number of liveborn individuals are born with a robertsonian translocation?
1 in 1000.
Can you get a homologous robertsonian?
Yes, but would be very rare. Formed from fusion of mat and pat homologues. Formation is typically postmeiotic.
More likely to be an isochromosome - formed from a single chromosome via misdivision of the centromere or U-type exchange.
What are the 2 types of inversions?
Pericentric - spans/contains the centromere and can alter shape of the chromosome and easier to spot.
Paracentric - confined to either long or short arm, can be very subtle.
Give an example of a common variant.
Inversion of chromosome 9, involves heterochromatic block around centromere.
Will be commented on in analysis but not reported.
What are the types of deletion?
Terminal - single break and material after break is lost, telomere must be healed for stability.
Interstitial - two breaks with loss of material between breaks.
What is a marker chromosome?
A chromosome of which no part can be identified. Seen at an increased frequency in mental retardation and subfertility.
What are the 2 most common marker chromosomes seen?
idic(15) or inv dup(15)
idic(22)
How are the idic(15) and idic(22) typically formed?
U-type exchange.
Inverted low copy repeats mediate the looping of one homologue round to join the other, the result is 1 x small dicentric chromosome and 1 x acentric larger fragment.
This can occur between chromatids or between homologous chromosomes.
The size of the fragments vary depending on which LCR is involved, ranging from heterochromatic to euchromatic.
This is FOLLOWED by a non-disjunction event so that the gamete receives 1 normal chr and the small idic.
What is important about a idic(15)?
Due to its origin it may contain the AS/PWS critical region.
Trisomies or tetrasomic dosage of this region correlates with abnormality including developmental delay, autism, epilepsy and minor physical defects.
What is significant about the idic(22)?
It is associated with Cat Eye syndrome.
How would you investigate a marker chromosome?
Most commonly originate from chr15 so FISH for the SNRPN, this probe consists of a CEP15 probe as well so will tell you whether it’s derived from 15 and if it contains AS/PWS critical region.
If not, next most likely is chr22 however we don’t have the probe. Would at this point do an array to determine if there is any euchromatic content.
If no euchromatic content then unlikely to be phenotypically relevant.
If you saw a heterochromatic marker chromosome in a male patient referred with fertility issues what would you think?
Could be contributing to the fertility issues but could be incidental. Marker chromosomes are reported more frequently in those with subfertility than in the general population but not enough to say it definitely causes infertility.
If we had a phenotypic patient who had a heterochromatic marker chromosome derived from 15 what could be a possible explanation?
That the remaining intact chromosomes are from the same parent and the patient has UPD15.
What is the most common cause of RECURRENT chromosome rearrangements? Name the different subtypes.
Non-allelic Homologous Recombination
Caused by either:
- Low Copy Repeats (LCR’s)
- Olfactory gene clusters e.g. t(4;8)(p16;p23)
- Palindromic AT-rich sequences e.g. t(11;22)(q23;q11)
What is the most common recurrent deletion that is due to LCR’s?
The 22q11.2 deletion that results in DiGeorge Syndrome.
What is a palindromic AT-rich sequence? What is significant about them?
Sequence that reads the same backwards and forwards, appear throughout the genome.
Causes the most common recurrent constitutional translocation in humans, the t(11;22)(q23;q11.2).
What are Low Copy Repeats (LCR)? What do they cause?
- Sequences that are similar to each other that are distributed throughout the genome (~10% of genome)
- They cause/allow erroneous coming together of different chromosome regions
- Misalignment of these sequences during meiosis sets stage for formation of translocations, deletions and duplications.
What are olfactory gene clusters? What in particular do they cause?
Repeat units found on different chromosomes across genome - they are associated with smell.
Similar regions that can allow erroneous recombination.
They cause a recurrent constitutional translocation - t(4;8)(p16;p23)
They are also implicated in the deletion polymorphisms seen on 4p and 8p and also recurrent deletion of 4p and 8p.
