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Yr 2 - EMS > Chromosome Pathology > Flashcards

Chromosome Pathology Flashcards

1
Q

How do chromosomal changes produce an abnormal phenotype? From commonest to rarest

A
  1. Dosage effect
  2. Disruption of a gene at a breakpoint
  3. Position effect
  4. Unmasking of a recessive disorder
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2
Q

What is ‘dosage effect’?

A

The number of copies of a particular gene present in a genome –> loss is usually worse than gain

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3
Q

What is ‘position effect’?

A

The effect on the expression of a gene when its location in a chromosome is changed, often by translocation

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4
Q

What is copy number variation?

A

When the number of copies of a particular gene varies from one individual to the next. There is a huge spectrum of sizes that can be lost or gained: - A whole chromosome (100 million base pairs) - All the way down to 1 base pair

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5
Q

Techniques used to detect different types of copy number variations:

A

Ranges from G-banding (larger additions/losses) down to Sanger sequencing (smaller additions/losses)

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6
Q

What are the types of CNV?

A
  • Chromosome number
    • Aneuploidy
    • Polyploidy
  • Chromosome structure
    • Deletion
    • Duplication
  • Mosaicism
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7
Q

What is aneuploidy?

A

The presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes

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8
Q

What is the most common type of aneuploidy?

A

Trisomy - there is an extra chromosome.

Examples:

  • Trisomy 21 (Down syndrome)
  • Trisomy 13 (Patau syndrome)
  • Trisomy 18 (Edwards syndrome)
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9
Q

What is monosomy?

A

Another type of aneuploidy in which there is a missing chromosome.

Example:

  • Turner syndrome - a female has a missing or damaged X chromosome.
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10
Q

What is polyploidy?

A

Polyploidy is a chromosomal mutation in which a cell has entire extra sets of chromosomes (the cells of an organism have more than two paired sets of chromosomes)

LETHAL

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11
Q

What is mosaicism?

A

Mosaicism is when a person has 2 or more genetically different sets of cells in his or her body. A person with mosaicism may have some cells in his or her body with 46 chromosomes. But other cells have 47 chromosomes.

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12
Q

How does maternal/paternal age affect aneuploidy?

A

Aneuploidy dramatically increases as women age (higher risk of having Down Syndrome baby the older you get)

Little or no paternal age effect

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13
Q

How does aneuploidy arise?

A

Errors in meiosis –> non-disjunction

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14
Q

What is non-disjunction?

A

Failure of homologous chromosomes or sister chromatids to separate during cell division (meiosis), so that both chromosomes go to one daughter cell and none go to the other.

  • This can arise from meiosis I (80-90%) or meiosis II (10-20%)
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15
Q

How does non-disjunction in meosis I differ from meosis II?

A

Meiosis I: failure of separation of homologous chromosomes

Meisosis II: failure of separation of sister chromatids

Nondisjunction results in daughter cells with abnormal chromosome numbers (aneuploidy)

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16
Q

Results of non-disjunction:

A

Disomic + normal –> fetal trisomy (may be viable)

Monosomic + normal –> fetal monosomy (lethal)

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17
Q

Presentations of Trisomy 21?

A

Down syndrome

Heart malformations

Learning difficulties

Gut atresias

Early dementia

Leukaemia

1/700

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18
Q

Presentations of Trisomy 13?

A

Patau Syndrome

Microcephaly

Holoprosencephaly

Clefting

Polydactyly

1/5000

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19
Q

Presentations of Trisomy 18?

A

Edwards syndrome

Microcephaly

Growth retardation

Rocker-bottom feet

Clenched hands

Cardiac anomalies

1/5000

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20
Q

What are the only viable aneuploidies?

A

13, 18, 21

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21
Q

What is sex chromosome aneuploidy?

A

A group of conditions in which individuals have an abnormal number of sex chromosomes.

Examples:

  • 47,XXY - Klinefelter’s syndrome
  • 47,XXX - Triple X syndrome
  • 45,X - Turner syndrome
22
Q

How do sex chromosome aneuploidies differ from autosomal aneuploidies?

A

Phenotype less severe than autosomal

  • Dosage compensation
  • Late diagnosis is common
23
Q

Presentation of Monosomy X

A

Turner Syndrome - 45,X

Short stature

Infertility

Primary amenorrhoea

Fetal/neonatal oedema

Neck webbing

Aortic coarctation

1/2500

24
Q

Polyploidy facts

A

Triploidy is most common (3 sets of chromosomes instead of 2)

  • 69XXY or 69,XYY or 69,XXX
  • 99.9% spontaneously abort
25
Q

What is G-banding?

A

A technique used in cytogenetics to produce a visible karyotype by staining condensed chromosomes.

26
Q

Why are chromosomes analysed at the metaphase stage of mitosois?

A

Chromosomes are analyzed at the metaphase stage of mitosis, when they are most condensed and therefore more clearly visible

27
Q

Does FISH or G-banding have a higher resolution?

A

FISH has a higher resolution

E.g. DiGeorge syndrome –> 2-Mbp deletion of chromsome 22q11.2

28
Q

What is chromosomal deletion?

A

Sometimes known as partial monosomies, occur when a piece or section of chromosomal material is missing. Deletions can occur in any part of any chromosome

29
Q

What is chromosomal duplication?

A

A type of mutation that involves the production of one or more copies of a region of a chromosome –> results in a trisomic region (n=3)

30
Q

What are the DNA-based methods for copy number?

A
  • Chromosomal microarrays (standard modern replacement for karyotyping)
  • Whole-genome sequencing
  • MLPA
  • Quantitative fluorescent PCR
31
Q

Advantages of chromosomal microarray vs karyotypes?

A

oOnly needs DNA, not live cells

oHigher resolution = much greater diagnostic hit rate

oAccurate location & size of imbalances (Defines gene content)

32
Q

Disadvantages of chromosomal microarray vs karyotype?

A

o Dosage changes only – not balanced rearrangements

o Low-level mosaics not detected

o Non-pathogenic & uncertain changes detected (unknown significance)

33
Q

CNV sequencing vs microarrays?

A

oResolution similar (~50 kbp)

oSimilar cost (£100)

oRobust to poor sample quality (from degraded DNA)

oCannot examine duplicated regions

34
Q

What does this cytogenic terminology mean?

  1. 47,XY,+21
  2. 46,XX,del(5)(q13q33)
  3. 46,XY,t(9;22)(q34;q11.2)
  4. 46,XX,dup(1)(q21q31)
A
  1. Extra chromosome 21
  2. Deletion within chromosome 5q
  3. Translocation between 9q34 and 22q11.2
  4. Duplication within chr. 1q
35
Q

What is a chromosomal inversion?

A

A segment of a chromosome is reversed end to end. An inversion occurs when a single chromosome undergoes breakage and rearrangement within itself. Inversions are of two types: paracentric and pericentric.

36
Q

Difference between pericentric and paracentric inversion?

A

Paracentric inversions: do not include the centromere and both breaks occur in one arm of the chromosome.

Pericentric inversions: include the centromere and there is a break point in each arm.

37
Q

What is cytogenics?

A

Cytogenetics is the study of chromosomal structure, location and function in cells. It includes the study of chromosome number and appearance (karyotyping), the physical location of genes on chromosomes, and chromosomal behaviour in processes such as cell division.

38
Q

What is reciprocal translocation?

A

A transfer of genetic material between homologous chromosomes. These are most commonly balanced exchanges, such that no genetic material is lost and individuals are phenotypically normal.

However, just like with inversions, abnormal phenotypes can be observed if the translocation breakpoint lies within a critical gene

39
Q

What happens during meiosis in reciprocal translocation?

A

The 4 chromosomes (2 translocated chromosomes and 2 normal homologous chromosomes) come together in a chromosome structure known as a ‘quadrivalent’ Two of these chromosomes then pass into the gamete. This maximises pairing. The chances are:

  1. The gamete contains the two normal chromosomes –> normal karyotype in the offspring
  2. The gamete contains the two derivative chromosomes –> offspring with the reciprocal balanced translocation (like the parent)
  3. The gamete contains one of the two derivates and one of the normal chromosomes –> offspring with monosomy for one region of the genome and trisomy for another.
40
Q

What are the 2 types of segregation during reciprocal translocation?

A

Alternate or adjacent

41
Q

What does alternate segregation during reciprocal translocation lead to?

A

Alternate segregation leads to gametes with either normal chromosomes (N1 and N2) or translocation chromosomes (T1 and T2); these gametes have a balanced set of chromosomes and will give rise to viable progeny.

42
Q

What does adjacent segregation during reciprocal translocation lead to?

A

Leads to unbalanced gametes (N1; T2 and N2;T1), since each gamete contains a large duplication and a large deletion.

43
Q

What is Robertsonian translocation?

A
  • Not an exchange of genetic material but a whole arm fusion
  • A chromosomal abnormality wherein a certain type of a chromosome becomes attached to another
  • It is the most common form of chromosomal translocation in humans
44
Q

How can a Robertsonian translocation lead to Down Syndrome?

A

A less common form of Down’s Syndrome (<5% of cases) is caused by a Robertsonian translocation between Chromosome 21 and Chromosome 14

High reccurence risk

45
Q

How is quantitative fluorescent PCR used to detect aneuploidy in pregnancy?

A

Is a method for rapid testing in urgent situations –> DNA extraction from prenatal sample:

  • Targetted at the clinically important aneuploidies
  • PCR amplification of STR loci on 13, 18, 21, X, Y
  • Aneuploidy detected as markers with abnormal dosage or numbre of alleles
46
Q

Example result of QF-PCR. What would this indicate?

A

Normal (two peaks so disomic 1:1)

47
Q

Example result of QF-PCR. What would this indicate?

A

Trisomy (2:1)

48
Q

Example result of QF-PCR. What does this indicate?

A

Trisomy (1:1:1) –> 3 different copies of chromosome 21

49
Q

Example result of QF-PCR. What does this indicate?

A

Uninformative (1:1 or 1:1:1)?

50
Q

What tends to cause a terminal gain (or loss) as shown here?

A

Unbalanced reciprocal translocations can cause terminal gains or losses

Look if there is another reciprocal terminal loss on another chromosome?

Yr 2 - EMS (60 decks)

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