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Flashcards in Chromosomal Abnormalities II Deck (24)
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Describe some major structural abnormalities and provide some named examples 


  • 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 
  • 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
  • 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 


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 


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

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