Chromosomal Abnormalities II Flashcards Preview

CLINICAL PATHOLOGY > Chromosomal Abnormalities II > Flashcards

Flashcards in Chromosomal Abnormalities II Deck (24)
Loading flashcards...
1
Q

Describe some major structural abnormalities and provide some named examples

A
  • Translocation
    • Robertsonian and Reciprocal
  • Inversion
  • Deletion (Terminal, interstitial)
  • Duplication
  • Rings
  • Isochromosomes
  • Microdeletions/Micropduplications
2
Q

Why do we get structural abnormalities in chromosomes?

A
  • 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
3
Q

What is a reciprocal translocation?

A

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

4
Q

What is a consequence of reciprocal translocation and via what mechanism does it occur?

A
  • 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
  • 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)
5
Q

What is the difference a balanced and unbalanced chromosomal translocation?

A

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

6
Q

Describe the philadelphia chromosome

A
  • Balanced reciprocal translocation affecting gene regulation
  • Translocation between Chr 9 + 22
  • Common cause of CML
  • Fusion of BCR-ABL gene = oncogene and causes cancer
7
Q

How is unbalanced offspring potentially produced from a balanced translocation?

A
  • 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
  • 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
  • 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
8
Q

What is the clinical result of an unbalanced reciprocal translocation?

A
  • 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
9
Q

What is a Robertsonian Translocation?

A

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

10
Q

What chromosomes are acrocentric?

A

The acrocentric chromosomes are 13, 14, 15, 21, and 22

11
Q

What are the features of robertsonian translocations?

A
  • 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
12
Q

What are common Robertsonian Translocations?

What translocation has a 100% risk of Down’s Syndrome in fetus?

A
  • Common translocations = 13;14, 14;21
  • 21;21 translocation leads to a 100% risk of Down’s Syndrome in foetus
13
Q

Why is the loss of the p arm not deleterious?

A

P arm encodes rRNA (there are multiple copies so its not deleterious to lose some)

We can happily exist as 45 chromosomes

14
Q

General outcomes of translocations

A
  • 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
15
Q

What is the significance of robertsonian translocation and trisomy 21?

A
  • 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
16
Q

What are the two ways in which Down’s Syndrome can occur?

A
  • 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
17
Q

Describe deletions

A
  • 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
18
Q

What is the consequence of a region of monosomy following a deletion?

A
  • Haploinsufficiency of some genes
  • Monosomic region has phenotypic consequences
  • Phenotype is specific for size and place on deletion
19
Q

Give an example of a syndrome caused due to a deletion

A

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
20
Q

What are microdeletions/microduplications and how are they detected?

A
  • 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
21
Q

Describe the process of array CGH

A
  • 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
22
Q

Provide some examples of microdeletion syndromes

A
  • Velocardiofacial 22q11
  • (DiGeorge, Shprintzen)
  • Wolf-Hirschhorn 4p16
  • Williams 7q11
  • Smith-Magenis 17p11
  • Angelman 15q11-13 (mat)
  • Prader-Willi 15q11-13 (pat)
23
Q

What is the mechanism by which (micro)deletions and (micro)duplications occur?

A
  • Deletions occur due to UNEQUAL CROSSING OVER resulting in non-allelic homologous recombination
  • This results in loss and gain of particular genes on chromosomes
24
Q

How can abnormal karyotypes be detected?

A
  • Large structural abnormalities

Detected by G-banding and FISH

  • Microdeletions and microduplications

Detected using array-CGH

Decks in CLINICAL PATHOLOGY Class (52):