Chromosomal Abnormalities II Flashcards
Describe some major structural abnormalities and provide some named examples
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Translocation
- Robertsonian and Reciprocal
- Inversion
- Deletion (Terminal, interstitial)
- Duplication
- Rings
- Isochromosomes
- Microdeletions/Micropduplications
Why do we get structural abnormalities in chromosomes?
- Double stranded DNA breaks can occur throughout the cell cycle
- These will generally be repaired through DNA repair pathways
- When there is an error/ mis-repair it will lead to structural abnormalities
What is a reciprocal translocation?
Exchange of two segments between two non-homologous chromosomes
e.g. Double stranded break on chromosome 1 and 22 which results in exchange and being stuck on the wrong chromosome
What is a consequence of reciprocal translocation and via what mechanism does it occur?
- There is no net gain or loss of material
- There is no deleterious phenotype unless the breakpoint affects the regulation of a gene
- e.g BCR-ABL oncogene
- There is no deleterious phenotype unless the breakpoint affects the regulation of a gene
- The carrier of a balanced translocation is at risk of producing unbalanced offspring
- Unbalanced individuals are at significant risk of a chromosomal disorder
- MECHANISM = Non-homologous end joining (NHEJ)
What is the difference a balanced and unbalanced chromosomal translocation?
Balanced = When you have the right amount of each chromosome but maybe not in the expected place
Unbalanced = When too much or too little of a particular chromosome
Describe the philadelphia chromosome
- Balanced reciprocal translocation affecting gene regulation
- Translocation between Chr 9 + 22
- Common cause of CML
- Fusion of BCR-ABL gene = oncogene and causes cancer
How is unbalanced offspring potentially produced from a balanced translocation?
- A reciprocal translocation means there is no loss or gain in material = little consequence of a cell carrying a reciprocal translocation
- However in meiosis, you may be lucky in the way that chromosomes separate is where the correct amount of each chromosome goes into the resultant cell
- However when reciprocal chromosomes pair up they form a pachytene quadrivalent as they search for their homologous pairs
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If they seperate along the horizontal line = one cell has a gain in first chromosome and loss in other end
- The daughter cell will have a loss of the end of the other chromosome and gain of the first chromosome
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If they seperate along the vertical line
- Unbalanced arrangement, where in each daughter cell there is loss at one end of a chromosome and gain at the other end
What is the clinical result of an unbalanced reciprocal translocation?
- Many lead to miscarriage (hence why a woman with a high number of unexplained miscarriages should be screened for a balanced translocation)
- Learning difficulties, physical difficulties
- Tend to be specific to each individual so exact risks and clinical features vary
What is a Robertsonian Translocation?
Exchange of material between two acrocentric chromosomes resulting in the loss of p arms and the bringing together of two q arms around a single centromere
What chromosomes are acrocentric?
The acrocentric chromosomes are 13, 14, 15, 21, and 22
What are the features of robertsonian translocations?
- Two acrocentric chromosomes join near centromere with loss of p arms
- A balanced carrier ends up with 45 chromosomes
- If 46 chromosomes are present, including robertsonian then must be unbalanced
What are common Robertsonian Translocations?
What translocation has a 100% risk of Down’s Syndrome in fetus?
- Common translocations = 13;14, 14;21
- 21;21 translocation leads to a 100% risk of Down’s Syndrome in foetus
Why is the loss of the p arm not deleterious?
P arm encodes rRNA (there are multiple copies so its not deleterious to lose some)
We can happily exist as 45 chromosomes
General outcomes of translocations
- Very difficult to predict
- Only have approximate probabillity of producing gametes
- Some unbalanced outcomes may lead to spontaneous abortion of concepts so early that not seen as problem
- Some unbalanced outcomes may lead to misscarriage later on
What is the significance of robertsonian translocation and trisomy 21?
- Upon fertilisation you can get a number of different possible combinations
- For example healthy copies of chromosome 14 and 21 ending in one gamete
- A robertsonian translocation between 14 and 21 will result in a carrier
- A 14/21 and 21 gamete = Down’s Syndrome
What are the two ways in which Down’s Syndrome can occur?
- Can occur due to a numerical abnormality via non-disjunction leading to three full copies of chromosomes
- Can occur due to a structural abnormality via a robertsonian translocation
Describe deletions
- Deletion may be terminal (at the end of a chromosome) or interstitial (in the middle of a chromosome)
- Causes a region of monosomy
- Haploinsufficiency of some genes
- Monosomic region has phenotypic consequences
- Phenotype is specific for size and place on deletion
- Gross/large deletions seen on metaphase spread on G-banded karyotype
- Causes a region of monosomy
What is the consequence of a region of monosomy following a deletion?
- Haploinsufficiency of some genes
- Monosomic region has phenotypic consequences
- Phenotype is specific for size and place on deletion
Give an example of a syndrome caused due to a deletion
Cri-du-chat syndrome
- Example of a chromosome deletion on chromosome 5
- Reffered to as partial monosomy or monosomy
- Characteristic cat like cty of affected children
What are microdeletions/microduplications and how are they detected?
- Microdeletion is a chromosomal deletion/ duplication smaller than 5 million base pairs
- Only a few genes may be lost or gained –> contigous gene syndrome
- Requires a high resolution for detection therefore can only be detected by FISH but mainly array-CGH
Describe the process of array CGH
- Patient and control DNA are labeled with fluorescent dye and applied to the microarray
- Patient and control DNA compete to attach, or hybridize to the microarray
- The microarray scanner measures the fluorescent signals
- There should be equal hybridisation however when there has been a duplication event there will be an excess of hybridisation of patient DNA
- There will be an excess of control DNA in a deletion event
Provide some examples of microdeletion syndromes
- Velocardiofacial 22q11
- (DiGeorge, Shprintzen)
- Wolf-Hirschhorn 4p16
- Williams 7q11
- Smith-Magenis 17p11
- Angelman 15q11-13 (mat)
- Prader-Willi 15q11-13 (pat)
What is the mechanism by which (micro)deletions and (micro)duplications occur?
- Deletions occur due to UNEQUAL CROSSING OVER resulting in non-allelic homologous recombination
- This results in loss and gain of particular genes on chromosomes
How can abnormal karyotypes be detected?
- Large structural abnormalities
Detected by G-banding and FISH
- Microdeletions and microduplications
Detected using array-CGH
