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SEM 4: Clinical Genetics > Chromosomal Abnormalities I > Flashcards

Chromosomal Abnormalities I Flashcards

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1
Q

Chromosome Structure

A

Chromosomes usually exists as chromatin. DNA double helix bounds to histones. Octamer of histones form nucleosome.

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2
Q

Euchromatin

A
  • Extended state, dispersed through nucleus

- Allows gene expression

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3
Q

Heterochromatin

A
  • Highly condensed, genes not expressed

- Tightly bound

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4
Q

Genetic locus

A

The location of a particular gene on a chromosome also can be defined as a genomic region.

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5
Q

What is located at the genetic locus?

A

At each genetic locus, an individual has two alleles, one on each homologous chromosomes.

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6
Q

Single chromosome and Double chromosome

A

In interphase, the chromosome is shown as a single chromatid. In S-phase, there is a doubling of DNA, with two duplicate chromatids which is also called a chromosome.

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7
Q

S phase (synthesis)

A
  • Go from single chromatid to double chromatid

- The allele to each loci on the chromatid is replicated identically.

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8
Q

Metacentric

A
  • p and q arm even length
  • 1-3 and 16-18
  • Centromere: In the middle of P+Q; important for telomeres to connect
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9
Q

Submetacentric

A
  • p arm shorter than q (p for petite)
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10
Q

Acrocentric

A
  • Long q and small p
  • P contains no unique DNA
  • 13-15, 21-22, Y
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11
Q

Karyotyping

A
  • Classic karyotyping is what is expected to be seen

- Easier to visualize as more condensed

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12
Q

Which cells don’t have 23 pairs of perfect chromosomes?

A

Gametes have 23 single chromosomes - Polychromic.

But ideally, every cell apart from the gametes will have 23 perfect pairs

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13
Q

What are the two types of chromosomal changes? How are these changes detected?

A
  • Numerical: can be detected through traditional karyotyping, FISH, QF-PCR, NGS
  • Structural: Can detect through traditional karyotyping, FISH
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14
Q

Haploid

A

One set of chromosomes (n=23) as in a normal gamete

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15
Q

Diploid

A

The cell contains two sets of chromosomes (2n = 46; normal in humans)

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16
Q

Polyploid

A

Multiple of the haploid number (e.g. 4n = 92)

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17
Q

Aneuploid

A

Chromosome number which is not an exact multiple of haploid number - due to extra or missing chromosome(s) e.g. 2n + 1 = 47 for example trisomies

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18
Q

Numerical Abnormalities

A
  • Trisomy: Aneuploidy
  • Monosomy: Aneuploidy
  • Mosaicism: Mixed group of cells; some may be aneuploidy and some are not.
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19
Q

Summarise meiosis 1 and 2

A

Allelic recombination
Important that homologous chromosomes align correctly Homologous Pairs are pulled apart = disjunction
2 rounds of division to form haploid daughter cells

20
Q

Disjunction

A

Pulling apart at anaphase

21
Q

Summarise mitosis

A
  • Single round
  • No alignment of HP
  • Generates diploid daughter cells that are identical to parents unlike meiosis
22
Q

How does aneuploidy arise?

A

Occur when there is non-disjunction = no separation.
Scenario 1)- this can be in one daughter cell that receives 2 chromosomes in meiosis 1.
- then in meiosis 2, there is a dizomic and the other has none.

Scenario 2) - Meiosis 1 is correct however, non-disjunction at meiosis 2 where there are two chromosomes in one daughter cell.

23
Q

What is formed when nondisjunction occurs?

A

There is a mixture of trisomy and monosomy whenever non-disjunction occurs. The implications depend on which chromosomes occur.

24
Q

What are some of the common aneuploidy abnormalities? What happens to most trisomies and monosomies?

A
  • Trisomy 13 - Pateau
  • Trisomy 18 - Edward’s
  • Trisomy 21 - Down’s
  • Autosomes are sensitive to most trisomies and monosomies so most will miscarry naturally.
25
Q

What causes mosacisim?

A

Mitotic non-disjunction

  • In the daughter cell, one will have 3 copies and the other 1 copy. This is perpetuated in future daughter cells.
  • Monosomies usually are broken down but some trisomies are maintained.
  • End up with a mixture of diploid and trisomic = mosaicism.
26
Q

Why is mosaicism important in terms of clinical presentation of diseases?

A

For example, in down’s - the disease is less severe if there are mosaic body cells.

27
Q

Define mosaicism

A

The presence of two or more genetically different cell lines derived from a single zygote.

28
Q

Apart from mitotic non-disjunction; what else can cause mosaicism?

A

Anaphase lag

29
Q

What is anaphase lag?

A
  • Same as trisomic rescue
  • Slow-down anaphase so doesn’t work properly
  • Meiotic NDJ -> every cell is trisomic but then during post-zygotic proliferation -> Anaphase is paused.
  • One of the chromosomes in the cell is removed in a vesicle.
  • This results in 2n rather than 2n +1. This causes a mixture again.
30
Q

Clinical relevance of Mosaicism

A
  • Mosaic phenotypes thought to be less severe
  • Difficult to asses the proportion of the different cells and which tissues/organs are affected
  • Difficult to predict the mosaicism that are seen in pretty much all chromosomal trisomies.
  • Examples of mosaic diseases: down, klinefelter and turner
  • Klinefelter and turners: Not diagnosed till after puberty or children- wanted.
31
Q

Monosomy

A
  • Autosomal are very rare - only one case reported which is thought to be a mistake.
  • Relatively common sex chromosome monosomy = Turner’s
  • Full monosomy arises by Meiotic NDJ
  • Partial Monosomy (microdeletion syndromes - can also lead to Turner’s) far more common
  • Pateau’s and Edward’s less likely to live as long.
  • Monosomy in autosomy doesn’t occur really. Less damaging to have multiple copies that it is to have one copy.
32
Q

How does Turner’s syndrome (45, X) arise?

A

1) Non-disjunction of chromosomes in Meiosis 1

2) So extra sex chromosomes in Meiosis 2 in an egg

33
Q

Nullisomic gametes

A
  1. Empty + X chr = XO = Turner’s (physically female)

2. Empty + Y chr = lethal

34
Q

Disomic gametes

A

XX

  1. XX + X chr = XXX = Triple X syndrome
  2. XX + Y chr = XXY = Klinefelter’s (physically male)

XY

  1. XY + X chr = XXY = Klinefelter’s
  2. XY + Y chr = XYY = XYY syndrome - thought to be associated with violence as a lot of male prisoners with violent crimes have this.
35
Q

Summary of numerical abnormalities

A
  • Types (all can be mosaic):
    • Autosomal: Trisomy 13, 18, 21
    • Sex chromosomes: XO, XXY, XYY
  • Mechanisms:
    • Nondisjunction
    • Anaphase lag
36
Q

How to find out a karyotype?

A
  1. Take blood
  2. Add Culture medium and phylomagglutinin
  3. Culture at 37 degrees for 3 days
  4. Add colchicine and hypotonic saline
  5. Cells will be fixed
  6. Spread cells onto slide by dropping (burst cells)
  7. Digest with trypsin and stain with Giernsa
  8. Analyse “metaphase spread”
  9. Forms a karyotype
37
Q

How to diagnose chromosome abnormalities prenatally?

A
  • Chorionic Villus Sampling
  • Amniocentesis
  • then the samples taken can be used to conduct a karyotype
38
Q

Chorionic Villus Sampling

A
  • 11-14 weeks
  • Miscarriage rate 0.5% to 1%
  • Maternal contamination
  • Transverse limb defects
  • Any invasive test is only done if there are limited risks e.g. age etc
  • Most chromosomal work is fetal
39
Q

Amniocentesis

A
  • > 16 weeks
  • Extraction of amniotic fluid
  • Biochemical diagnosis possible
  • Miscarriage risk (0.5 - 1%)
  • Not used as a definitive but cells are cultured
40
Q

G-banding

A
  • Uses a Giemsa stain (G = Giemsa)
  • Metaphase of chromosomes shown
  • Classical karyotyping methodology
  • Line-up based on size, banding, centromere position
  • The difference in band colour is to do with hetero (dark) and euchromatin (light).
  • Heterochromatin: AT-rich; tightly packed; genes inactive
  • Euchromatin: GC-rich; loosley packed; genes active
  • Both stain differently
41
Q

What is FISH?

A

Fluorescent in situ hybridization

  • Cultured cells
  • Microscopic (5-10Mb) - detects for deletions to this size anything smaller won’t be detected.
42
Q

How is FISH carried out?

A
  1. Fluorescent probe
  2. Denature probe and target DNA (typically single-stranded DNA probe)
  3. Mix probe and target DNA
  4. The probe binds to target
  5. Using UV light, the probe will glow.
43
Q

What are some uses of fluorescence in chromosome testing?

A
  • Spectral karyotyping = multiple probes looking over the whole chromosome
  • Target specific FISH
44
Q

What is a quicker test for trisomy?

A

Quantitative fluorescence PCR

- Using microsatellites

45
Q

Examples of invasive prenatal diagnosis testing

A
  • Amniocentesis (14-20 wks, amniotic fluid)

- Chorionic villus sampling (CVS) (11-14 wks, placental cells)

46
Q

Examples of non-invasive prenatal diagnosis testing

A
  • Cell-free foetal DNA (cffDNA): DNA fragments in maternal plasma (10 wks onwards) -> extract foetal DNA from maternal plasma by extracting and enriching plasma
  • Actually for trisomies still need confirmation with amnio/CVS
47
Q

How is the DNA from cffDNA used?

A
  1. Can use standard PCR to amplify the gene in the cffDNA from foetal DNA.
  2. Can use next-gen sequencing and capture foetal DNA that reads across the entire genome and will produce equal coverage.

SEM 4: Clinical Genetics (5 decks)

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