Chromosomal Abnormalities I Flashcards Preview

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Flashcards in Chromosomal Abnormalities I Deck (23)
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1
Q

Describe the normal human chromosome number

A

46 Chromosomes

22 pairs and 1 pair of sex Chromosomes

2
Q

What is a karyotype

A

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
Q

Describe the normal structure of chromosomes

A
  • 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
Q

Why do we visuallise chromosomes at the metaphase stage?

A

Because they are most condensed

5
Q

What are metacentric, submetacentric and acrocentric chromsomes?

A

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
Q

What type of chromosomes are the X and Y chromosome?

A

X chromosome = Submetacentric

Y chromosome = Acrocentric

7
Q

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

How can they be detected?

A
  1. Numerical - can detect through karyotyping, FISH, QF-PCR, NGS
  2. Structural - detect through karyotyping and FISH
8
Q

Define Haploid, Diploid and Polyploid

A
  • 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
Q

Define Aneuploidy

A

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
Q

Define three classic autosomal aneuploidies

A
  • Trisomy 13 (Patau Syndrome)
  • Trisomy 18 (Edward’s Syndrome)
  • Trisomy 21 (Down’s Syndrome)
11
Q

List some examples of aneuploid numerical abnormalities

A
  • 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
Q

Via what mechanism does aneuploidy arise?

A

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
Q

What are the two mechanisms of mosaicism?

A
  • 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
Q

Describe mitotic/ post-zygotic non-disjunction

A
  • 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
Q

Describe anaphase lag?

A
  • 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
Q

What is the clinical relevance of mosaicism?

A
  • 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
Q

Describe the different types of monosomies

A
  • 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
Q

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

A
  • 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
Q

What are the ways of analysing chromosomal abnormalities?

A

Postnatal

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

Prenatal

  • CVS, aminocentesis or cffDNA & NGS
20
Q

Describe chorionic villus and aminocentesis sampling

A

→ 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
Q

How can FISH and qPCR be used for analysis?

A
  • 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
Q

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)

A

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
Q

List common trisomies including their karyotype

A
  • 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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