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Clinical Genetics > Chromosomal Abnormalities II > Flashcards

Chromosomal Abnormalities II Flashcards

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1
Q

Outline structural chromosomal abnormalities

A
  • Translocations
    - Reciprocal
    - Robertsonian
  • Inversion
  • Deletion
  • Duplication
  • Rings
  • Isochromosomes
  • Microdeletions/Microduplications
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2
Q

Outline the mechanism of structural changes in chromosomes

A
  1. Double strand DNA breaks
  2. Occur throughout cell cycle
  3. Generally repaired through DNA repair pathways in G2 phase
  4. Mis-repair leads to structural abnormalities
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3
Q

What are reciprocal translocations?

A

chromosomes

> So mechanism is called Non-Homologous End Joining (NHEJ)

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4
Q

Give an example of non-homologous end joining

A
  1. Plus copy of normal 1 and normal 22
  2. Double strand break occurs at chr.1 and chr.22
  3. Due to close proximity chr.1 segment joins onto chr.22
    and vice versa forming derivative chromosomes (der)
  4. Carrier of balanced translocation = normal copy of both
    chr. 1 and chr.22 present as well as derivatives
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5
Q

What are derivative chromosomes?

A

Derivative chromosomes are a mixture of 2 chromosomes

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6
Q

What is meant by a balanced translocation?

A

No net gain or loss of genetic material - have right amount just in incorrect place

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7
Q

What is NHEJ?

A

The DNA repair mechanism is called “non-homologous end joining”: joins together two ends irrespective of DNA sequence joined together - balanced translocations

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8
Q

When does NHEJ occur?

A

Forms spontaneously during meiosis

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9
Q

Give an example of a ‘harmful’ balanced translocation?

A

Philadelphia chr = abnormal chr22

Leads to Chronic myeloid leukaemia (CML)

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10
Q

What loci are involved in the philadelphia gene translocation?

A

BCR = breakpoint cluster region on Chr.22 (Function of normal protein product not known)

ABL = protooncogene

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11
Q

Outline how philadelphia gene leads to CML

A

Reciprocal translocation occurs and they’re brought together to generate a fusion gene (BCR-ABL)
The BCR activates the ABL to become an oncogene which leads to uncontrolled cell division and cancer

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12
Q

When do reciprocal translocations produce deleterious phenotypes?

A

Usually no deleterious phenotype unless breakpoint affects regulation of a gene

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13
Q

What is the consequence of unbalanced translocations?

A

Carrier of balanced translocation at risk of producing unbalanced offspring

Unbalanced individuals at significant risk of chromosomal disorder

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14
Q

How do homologous chromosomes normally create genetic variation during meiosis?

A

Homologous chromosomes line up during metaphase I in meiosis to form bivalents in order to exchange material

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15
Q

How is crossing over affected in derivative chromosomes?

A

Derivative chromosomes form quadrivalents rather than bivalents

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16
Q

How does a reciprocal translocation effect DNA content?

A

Reciprocal translocation means no material loss / gain ⇒ often little consequence to the cell carrying a reciprocal translocation.
However – that changes during meiosis.

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17
Q

Describe how no net gain / loss can occur in reciprocal translocation offspring?

A

In meiosis, the chromosomes may separate where the correct amount of each chromosome goes into the resultant cell

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18
Q

Why is no net gain/loss unlikely to occur in reciprocal translocation offspring?

A

Before separating, chromosomes line up forming a structure called a pachytene quadrivalent and separate unequally

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19
Q

What is the consequence of quadrivalent formation in meiosis?

A

Results in an unbalanced arrangement where, in each daughter cell, there is loss of one end of a chromosome and gain of the end of the other chromosome.

20
Q

What is the effect of inheriting an unbalanced chromosome?

A

The exact consequences of inheriting a unbalanced rearrangement depend on the particular chromosomes involved and the size of the translocated material

21
Q

Describe the clinical results of unbalanced reciprocal translocations

A
  • Many lead to miscarriage
    (women with a high no. of unexplained miscarriages should be screened for balanced translocation)
  • Learning difficulties, physical disabilities
  • Specific to each individual; risks + clinical features vary
22
Q

What are robertsonian translocations?

A

Loss of satellites due to only the long arms being joined together again after chromosomes break at / near their centromeres

23
Q

Describe no. of chromosomes in a robertsonian carrier

A

Balanced carrier has 45 chromosomes

If 46 chromosomes present including Robertsonian then must be unbalanced

24
Q

What is the net loss of genetic material in robertsonian translocations?

A

The only genetic material lost are satellites; p arms encode rRNA (multiple copies so not deleterious to lose some)

25
Q

Which type of chromosomes are affected by robertsonian translocations?

A

Only affects acrocentric chromosomes – centromere near chromosome tip (Chr. 13, 14, 15, 21 & 22)

26
Q

What are common robertsonian translocations?

A

Robertsonian translocations 13;14 and 14;21 relatively common. 21;21 translocation leads to 100% risk of Down syndrome in fetus

27
Q

What is a centromere?

A

Part of chromosome attaching to the spindle during cell division; not always in the middle.

28
Q

What are the 5 acrocentric chromosomes?

A

Of note is the fact that there are 5 acrocentric chromosomes: 13, 14, 15, 21 and 22.

29
Q

What are the normal outcomes of a robertsonian translocation between chromosomes 14 and 21?

A
  1. Daughter cell end up w/ normal chr. 14 and 21: gamete can form normal child after fertilisation
  2. Daughter cell only has translocated chromosome: gamete capable of forming a normal child
30
Q

How does a robertsonian translocation between chromosomes 14 and 21 cause Downs?

A
  1. Chromosomes segregate
  2. Daughter cell contains normal chr. 21 and translocated
    chromosome
  3. After fertilisation, these are joined by another chr. 14
    and chr. 21 = normal no. of chr. 14, but trisomy of
    chromosome 21.

⇒ Down’s syndrome

31
Q

How do lethal combinations of robertsonian translocations between Chr. 14 and 21 occur?

A

Other chromosome segregations will result in monosomy of one of the chromosomes or trisomy 14 – all incompatible with life

32
Q

Explain how robertsonian translocations can lead to msicarriage

A

Couples where one partner is a carrier of a Robertsonian translocation can experience multiple miscarriages because of the way the chromosomes segregate, leading to loss of a chromosome or a trisomy which is incompatible with life

33
Q

Outline the numerical and structural causes of Trisomy 21 Downs syndrome

A

Trisomy 21 due to NDJ
3 full copies - numerical abnormality

Trisomy 21 due to Robertsonian Translocation
Chr.21 also on chr.14 as well as 2 normal copies of chr.21 leading to a trisomy - structural abnormality

34
Q

Outline the outcomes of unbalanced translocations

A
  • Spontaneous abortion of conceptus; so early its not seen as problem
  • Miscarriage later on and present clinically
  • Live-born baby with various problems
35
Q

How can we fix a chr. that has lost an end?

A

If end of a chr. is lost, only way to make it stable is adding a new telomere; without the telomere the cell will die

36
Q

What is duplication?

A

Duplication - a region of chromosome is repeated e.g. globin gene family

37
Q

What is inversion?

A

Inversion - 2 breakpoints within the same chromosome and when repaired the middle section is “upside down”

38
Q

What is a ring chromosome?

A

A ring chromosome - two breaks in the same chromosome and that non-homologous end joining mechanism joins the two ends of the large chunk together, resulting in a ring

39
Q

What are the effects odf chromosome deletions?

A

Deletion may be terminal or interstitial
Causes a region of monosomy
- Haploinsufficiency of genes
- Monosomic region has phenotypic consequences
- Phenotype specific for size + place on deletion

40
Q

How can we view gross deletions?

A

Gross deletions seen on metaphase spread on G-banded karyotype

41
Q

How are microdeletions visualised?

A

Many patients had no abnormality visible on metaphase spread

High resolution banding, FISH and now CGH showed ‘micro’ deletions

42
Q

What are microdeletions / microduplications?

A

Only a few genes may be lost or gained – contiguous gene syndrome

43
Q

Outline common microdeletion syndromes

A 
Velocardiofacial	22q11(DiGeorge, Shprintzen)
Wolf-Hirschhorn	4p16
Williams		        7q11
Smith-Magenis	17p11
Angelman		15q11-13 (mat)
Prader-Willi		15q11-13 (pat)
44
Q

What is the effect of non-allelic crossing over?

A

Non-allelic unequal crossing over occurs causing a loss / gain of loci on resulting gametes
2 are altered while 2 are normal (causing deletions or duplications)

45
Q

What is array cgh?

A

Microarrays created by deposit and immobilization of probes on a solid support
e.g. glass slide, in an ordered fashion.

46
Q

How big are array CGH probes?

A

Probes vary in size from oligonucleotides;areas of interest (25–85 base pairs) to genomic clones;bacterial artificial chromosomes (80,000–200,000 base pairs)

Clinical Genetics (5 decks)

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