Chromosomal Abnormalities I Flashcards Preview

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Flashcards in Chromosomal Abnormalities I Deck (23)
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1

Describe the normal human chromosome number 

46 Chromosomes  

22 pairs and 1 pair of sex Chromosomes 

2

What is a karyotype 

Is the chromosomal constitution of the cell nucleus (photomicrograph of the chromosomes arranged)

  • G-bandings allows us to look at the karyotype 
  • Stain chromosomes with Gisema stain in METAPHASE 
    • - Euchromatin = GC-rich, loosely packed, genes active 
    • - Heterochromatin = AT-rich, tightly packed, genes inactive 
    • Stain differently allowing us to see the banding pattern 

Line up based on: 

  • Size 
  • Banding 
  • Centromere position 

 

3

Describe the normal structure of chromosomes

  • Chromosomes will require a centromere and telomere to survive 
  • Chromosomes are called p (petite) and q arm 
    • P =short arm, q = long arm 
  • Chromosomes will usually exist as chromatin 
  • DNA double helix bound to histones 
  • Octamer of histones form nucleosome 
  • Chromosomes will exist as homologous parts and have a maternal and paternal copy 
    • Homologs will have the same genes on them however they may have different allelic forms 

4

Why do we visuallise chromosomes at the metaphase stage? 

Because they are most condensed 

5

What are metacentric, submetacentric and acrocentric chromsomes? 

Metacentric (p and q same length) 

  • 1-3, 16-18 

Submetacentric (p arm shorter than q) 

  • 4-12, 19-20, X

Acrocentric (long q, small p) 

  • p contains no unique DNA 
    • genes on satellite arms code for same set of rRNA molecules) 
  • 13-15, 21-22, Y 

6

What type of chromosomes are the X and Y chromosome? 

X chromosome = Submetacentric 

Y chromosome = Acrocentric 

7

What are the two types of chromosomal abnormalities which can occur? 

How can they be detected? 

  1. Numerical - can detect through karyotyping, FISH, QF-PCR, NGS
  2. Structural - detect through karyotyping and FISH 

8

Define Haploid, Diploid and Polyploid 

  • HAPLOID:
    • one set of chromosomes (n=23) as in a normal gamete.
  • DIPLOID:
    • cell contains two sets of chromosomes (2n=46; normal in human)
  • POLYPLOID:
    • multiple of the haploid number (e.g. 4n=92)

9

Define Aneuploidy

Chromosome number that is not an exact multiple of haploid number due to extra or missing chromosomes e.g a cell having 45 or 47 chromosomes 

10

Define three classic autosomal aneuploidies

  • Trisomy 13 (Patau Syndrome) 
  • Trisomy 18 (Edward's Syndrome) 
  • Trisomy 21 (Down's Syndrome) 

11

List some examples of aneuploid numerical abnormalities 

  • Trisomy - three chromosomes in a cell (2n+1) 
  • Monosomy - one chromosome in a cell 
  • Mosaicism - two or more populations of cells with different genotypes in one individual 
    • E.g turner syndrome, some cells will be XO and some will be XX 

12

Via what mechanism does aneuploidy arise? 

Aneuploidy arises via NON-DISJUNCTION 

 

This is where the homologues will not pull apart and both go onto the same cell 

In meiosis I = Two diploid cells 

In meiosis II = 2 haploid cell and 1 diploid cell 

13

What are the two mechanisms of mosaicism? 

  • Post-zygotic nondisjunction/mitotic non-disjunction 
    • All cells start as 2n and go to a mixture of 2n and 2n+1
  • Anaphase lag 
    • Trisomic rescue = all cells start as 2n+1 then go to a mxture of 2n+1 and 2n 

14

Describe mitotic/ post-zygotic non-disjunction 

  • Occurs as a result of the chromatids which are not seperating properly in mitosis resulting in a mixed population of cells with respect to the genomic material 
  • Some cells are trisomic and other cells are disomic 

15

Describe anaphase lag? 

  • In the process of anaphase there may be a delay/pause in the pulling part of one of the chromosomes
  • A membrane will form around this individual chromosome which will essentially be rescued from trisomy due to the delay (note: its not a repair process) this will then be degraded
  • This allows for a mixed population of cells where some are disomic and other cells are trisomic
  • This essentially rescues some of the cells from being trisomic (hence trisomic rescue)

16

What is the clinical relevance of mosaicism? 

  • Mosaic forms are thought to be less severe

 

  • However difficult to asses 
    • What are the proportions of the different cell types?
    • Which tissues/organs are affected? 
  • Examples 
  • Downs = 2% Trisomy 21
  • Klinefelter = 15% (48XY/ 47XXY)
  • Turner = Up to 25%

 

 

17

Describe the different types of monosomies

  • Autosomal monosomies are very rare 
    • This is because they are not consistent with life 
  • Sex Chromosome monosomy is very common e.g Turner's XO 
  • All full monosomies arise via non-disjunction 
  • Partial monosomies (microdeletion syndromes (more common) thought to arise via a different mechanism) 

18

Considering how Turner's arises (45X), what are some possible combinations of chromosomes in monosomies 

  • NULLISOMIC GAMETES
    • + X Chr = XO = Turner’s (physically female)
    • + Y Chr = lethal (not consistent with life)
  • DISOMIC GAMETES
  • XX
    • + X Chr = XXX = Triple X syndrome
    • + Y Chr = XXY = Klinefelter’s (physically male)
  • XY
    • + X Chr = XXY = Klinefelter’s
    • + Y Chr = XYY = XYY Syndrome

19

What are the ways of analysing chromosomal abnormalities? 

Postnatal 

  • Blood samples 
    • Take blood and look at chromosomes in the metaphase stage

Prenatal 

  • CVS, aminocentesis or cffDNA & NGS 

20

Describe chorionic villus and aminocentesis sampling 

→ Chorionic Villus Sampling (cells removed from placenta) 

11-14 weeks, Miscarriage rate 0.5%-1%, can be Maternal Contamination and can cause Transverse Limb defects

→ Aminocentesis

>16 weeks, extraction of amniotic fluid, biochemical diagnosis possible, miscarriage risk (0.5-1%)

21

How can FISH and qPCR be used for analysis? 

  • quantitative flouorescence PCR 
    • Primers are designed for specific microsatellitemarkers on chromosome 21
    • These regions are amplified and copies will be assesed on their size 
    • In diagram you can see three peaks = 3 chromosomes 
  • FISH 
    • Flurorescent probes will bind to target DNA on chromosomes 

22

What are some ways we can get pre-natal diagnosis which is not invasive? 

 

(Aminocentesis and Chorionic Villus sampling can increase the risk of a miscarriage) 

Cell free foetal DNA (cffDNA) 

  • DNA fragments in maternal plasma (10 weeks onwards) 
  • Foetal DNA seperated and further tests are carried out such as 
    • PCR
    • NGS 

23

List common trisomies including their karyotype

  • Patau 47 - trisomy 13
    • XX+ 13, XY+ 13 
  • Edwards 47 - trisomy 18
    • XX+ 18, XY + 18 
  • Downs 47 - trisomy 21
    • XX + 21, XY + 21
  • Turner's = 45 XO 
  • Klinefelter 47 XXY 

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