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Fundamentals of P > Chromosomal abnormalities II > Flashcards

Chromosomal abnormalities II Flashcards

1
Q

Structural abnormalities - list 7 types

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

Describe formation of structural abnormalities

A

Double strand DNA breaks

Occur throughout cell cycle

Generally repaired through DNA repair pathways

Mis-repair leads to structural abnormalities

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3
Q

Reciprocal Translocations - define

A

Exchange of two segments between non-homologous chromosomes

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

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4
Q

Reciprocal Translocations - reason for its name = “non-homologous end joining”

A

The DNA repair mechanism is called “non-homologous end joining”: end joining because it’s joining together two ends and non-homologous because it’s irrespective of the DNA sequence joined together

These are also known as balanced translocations

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5
Q

Reciprocal Translocations - when

A

It’s thought that they form spontaneously during meiosis

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6
Q

Reciprocal Translocations - key characteristic

A

The key characteristic is that there is no net gain or loss of genetic material – it’s all there, just in a different place.

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7
Q

Reciprocal Translocations - which chromosomes involved

A

They can involve any chromosome and the fragments can be of any size

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8
Q

Reciprocal Translocations - incidence

A

They are relatively common – estimates suggest that they occur in 1 in 930 people

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9
Q

Balanced vs Unbalanced translocations

A

Balanced = have the right amount of each chromosome just maybe not in the expected place!

Unbalanced = too much or too little of a particular chromosome

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10
Q

Effect on carriers of balanced translocation - example

A

Philadelphia chr = abnormal chr22
Leads to Chronic myeloid leukaemia (CML)
ABL fuses w/BCR

BCR=breakpoint cluster region (Function of normal protein product not known)
ABL=protooncogene
Fusion of genes leads to an activated oncogene

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11
Q

Balanced translocation - define

A

Balanced translocation – no net gain or loss of material

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12
Q

Reciprocal Translocations - define

A

Exchange of two segments between non-homologous chromosomes

no loss or gain of material

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13
Q

Reciprocal Translocations - effect on phenotype

A

Usually no deleterious phenotype unless breakpoint affects regulation of a gene

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14
Q

Reciprocal Translocations - effect on carriers

A

Carrier of balanced translocation at risk of producing unbalanced offspring

Unbalanced individuals at significant risk of chromosomal disorder

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15
Q

How are unbalanced individuals produced?

A

Balanced carrier to unbalanced zygote

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16
Q

Consequences of reciprocal translocations

in meiosis

A

Chromosomes pair up before separating, form = pachytene quadrivalent = CS A + B with C + D (example)

CS separate along horizontal line, = one cell having a gain in A/B CS and a loss of the end of C/D CS;

the other daughter cell has a loss of the end of the A/B CS and gain of C/D

OR CS could separate along this vertical line

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

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17
Q

The exact consequences of inheriting a unbalanced rearrangement depend on what

A

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

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18
Q

Clinical result of unbalanced reciprocal translocation

A

Many lead to miscarriage (hence why a woman with a high number of unexplained miscarriages should be screened for a balanced translocation)

Learning difficulties, physical disabilities

Tend to be specific to each individual so exact risks and clinical features vary

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19
Q

Robertsonian translocation - define

A

When two acrocentric chromosomes break at or near their centromeres, when the fragments are joined together again it’s possible for just the two sets of long arms to be brought together and there’s loss of the satellites.

20
Q

Robertsonian translocation - resulting number of CS

A

45

21
Q

Robertsonian translocation - what is lost

A

The only genetic material we’ve lost are these satellites and the cell can do without those and so this isn’t a problem for the cell.

22
Q

Robertsonian translocation - which CS effected

A

Only affect acrocentric chromosomes – ie. Those which have the centromere near the chromosome tip. These are chromosomes 13, 14, 15, 21 & 22

23
Q

Robertsonian translocation - most common type + its result

A

Most common Robertsonian translocation involves chromosomes 13 and 14, which accounts for approximately 1/3 of all Robertsonian translocations

Results in loss of two short arms and fusion of the two long arms, with either one or two centromeres

The resultant chromosome usually contains the long arms of different chromosomes

24
Q

What’s the centromere?

A

It’s the part of the chromosome which attaches to the spindle during cell division.

25
Q

Robertsonian translocation - explain effect (balanced vs unbalanced)

A

Two acrocentric chromosomes join near centromere with the loss of p arms

Balanced carrier has 45 chromosomes

If 46 chromosomes present including Robertsonian then must be unbalanced

p arms encode rRNA (multiple copies so not deleterious to lose some)

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

26
Q

Robertsonian Translocation & Trisomy 21 - effect where one partner is carrier of robertsonian translocation

A

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

27
Q

Robertsonian Translocation & Trisomy 21 - combinations and their effect

A

If you’re lucky, the gamete will contain the normal chromosomes, or the robertsonian chromosome

If you’re unlucky then the gamete will contain one of these combinations.

Most of them will be lethal

But upon fertilisation with a normal gamete, this cell will have 2 copies of chromosome 14, which is fine, but 3 copies of chromosome 21 – and will therefore be a Down’s baby.

This will be a “normal” Down’s baby in that the phenotype will be similar to a Down’s which is the product of non-disjunction.

28
Q

Robertsonian Translocation & Trisomy 21 - when does it become a problem

A

However, it becomes a problem in the context of forming gametes, because although there’s the correct amount of genetic material, the chromosomes can’t segregate properly.

29
Q

Outcomes of translocations

A

Very difficult to predict
- Only have approximate probability of producing possible gametes

Some unbalanced outcomes may lead to spontaneous abortion of conceptus so early that not seen as problem

Some unbalanced outcomes may lead to miscarriage later on and present clinically

Some may result in live-born baby with various problems

30
Q

If the end of the chromosome is lost then the only way the chromosome can be made stable is what

A

If the end of the chromosome is lost then the only way the chromosome can be made stable is if a new telomere is added; without the telomere the cell will die

31
Q

Inversion - define

A

An inversion is where there are two breakpoints within the same chromosome and when these are repaired the middle section is “upside down”

32
Q

Duplication - define

A

A duplication is where you get a region of the chromosome repeated – you’ll probably be familiar with this in terms of the globin gene family

33
Q

Ring CS - define

A

A ring chromosome is where you get 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.

34
Q

Deletions - incidence of effect

A

1:7000 live births

35
Q

Deletions - list types

A

Deletion may be terminal or interstitial

36
Q

Deletions - genetic effect

A

Causes a region of monosomy

  • Haploinsufficiency of some genes
  • Monosomic region has phenotypic consequences
  • Phenotype is specific for size and place on deletion
37
Q

Deletions in relation to G-band

A

Gross deletions seen on metaphase spread on G-banded karyotype

38
Q

Cri-du-chat - define

A

Genetic condition present from birth that is caused by the deletion of genetic material on the small arm (the p arm) of chromosome 5

39
Q

Cri-du-chat - effect

A

ID, developmental delay, microcephaly

40
Q

Microcephaly - define

A

Microcephaly is a condition where the head (circumference) is smaller than normal

41
Q

Microcephaly - cause

A

By genetic abnormalities or by drugs, alcohol, certain viruses, and toxins that are exposed to the fetus during pregnancy and damage the developing brain tissue.

42
Q

Microdeletions/Microduplications on metaphase spread

A

Many patients had no abnormality visible on metaphase spread

43
Q

Microdeletions/Microduplications - result on from FISH, HRB and CGH

A

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

44
Q

Contiguous gene syndrome - define

A

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

A clinical phenotype caused by a chromosomal abnormality, such as a deletion or duplication that removes several genes lying in close proximity to one another on the chromosome.

45
Q

Microdeletion syndromes - list 6

A 
Velocardiofacial			22q11
(DiGeorge, Shprintzen)
Wolf-Hirschhorn			4p16
Williams					7q11
Smith-Magenis			17p11
Angelman				15q11-13 (mat)
Prader-Willi				15q11-13 (pat)
46
Q

Array CGH - describe process

A

Pt and control DNA labelled w/fluorescent dyes and applied to microarray

Attached/hybridized to microarray

Microarray scanner measures fluorescent signals

Computer software analyzes data and generates plot

Fundamentals of P (62 decks)

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