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Clinical Genetics > Chromosomal Abnormalities II > Flashcards

Chromosomal Abnormalities II Flashcards

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1
Q
  1. What are some examples of structural Abnormalities?
A
  • Translocations: Reciprocal or Robertsonian
  • Inversion, Deletion, Duplication
  • Rings
  • Isochromosomes
  • Microdeletions/Microduplications
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2
Q
  1. How do structural abnormalities occur?
A

•Double strand DNA breaks occur throughout cell cycle and are generally repaired through DNA repair pathways. Mis-repair leads to structural abnormalities.

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3
Q
  1. How do reciprocal Translocations occur?
A
  • Non-Homologous End Joining (NHEJ): Exchange of two segments between non-homologous chromosomes.
  • Derivative chromosomes (chromosomes that are a mixture of 2) are usually not a problem and are common.
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4
Q
  1. What happens if the result of a reciprocal translocation is:
    -Balanced
    or
    -Unbalanced
A
  • Balanced: have the right amount of each chromosome (no net gain/loss of material), just not in the expected place!- Usually no deleterious phenotype unless breakpoint affects regulation of a gene.
  • Unbalanced = too much or too little of a particular chromosome- Unbalanced individuals at significant risk of chromosomal disorder.
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5
Q
  1. What are two RISKS associated with having balanced chromosomes after a reciprocal translocation?
A

oCarriers of balanced translocations (ch9 and ch22) are not always lucky e.g. the Philadelphia chromosome leading to Chronic Myeloid Leukaemia due to the BCR-ABL fusion gene.

oCarrier of balanced translocation at risk of producing unbalanced offspring.

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6
Q
  1. How can we go from a balanced carrier to unbalanced zygote ( unbalanced individual being produced)
A

Homologous chromosomes align in metaphase 1 in bivalent (homologous pairs)

But how can derivative chromosomes align with their homologue - they dont have one . End up producing unbalanced daughter cells

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7
Q
  1. What is a pachytene quadrivalent ?
A

At meiosis, a balanced reciprocal translocation may not be able to pair up correctly. Instead of paring in ‘two’s’ with the other same number chromosome, the balanced translocation ends up pairing in fours; known as a pachytene quadrivalent.

- 4 possible outcomes :
balanced
normal
partial trisomy + partial monosomy
Partial monosomy + partial trisomy
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8
Q
  1. What is the consequence of reciprocal translocation in meiosis?
A
  • During meiosis, balanced derivative form a pachytene quadrivalent structure before separation during anaphase (separation of opposite chromosomes – balanced).
  • Separation can happen along the horizontal line or along the vertical line to produce chromosomes of an unbalanced arrangement (loss at end of one chromosome and gain at the end of another).
  • The consequences of inheriting unbalanced chromosomes depend on the particular chromosome (genes) involved and the size of the material that has been translocated.
  • When the unbalanced gametes are fertilised, they form cells with partial trisomy and partial monosomy.
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9
Q
  1. What are some clinical results of unbalanced reciprocal translocations?x
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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10
Q
  1. What are Robertsonian Translocations?
A

•Two acrocentric (loss of p arms) chromosomes break near their centromeres and their long arms are re-joined
In essence, two half chromosomes ( of just q arms) are made into one chromosome (both p and q arms)

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11
Q
  1. Is Robertsonian Translocations dangerous ?
A

These cells have 45 chromosomes and are not always disease causing because the p arms encode rRNA (multiple copies so not deleterious to lose some).
•Unbalanced If 46 chromosomes are present including Robertsonian.

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12
Q
  1. What are some common robertsonian translocation?
A

13;14 and 14;21 relatively common

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13
Q
  1. Which robertsonian translocation is guaranteed to result in Down syndrome?
A

21;21 translocation leads to 100% risk of Down syndrome in foetus.

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14
Q
  1. What is the consequence of Robert translocation of chromosome 14 and 21?

A healthy, balanced individual has a normal ch14 and a normal ch21 but a translocated derivative of ch14/21
•These chromosomes form a trivalent structure which can result in 4 possibilities ?

A
  1. Normal person (normal 14 and 21)
  2. Normal carrier (balanced derivative)
  3. Down’s (derivative and ch21)
  4. Lethal (just 14 or 21 OR 14 and derivative).

•Upon fertilisation – you will have 2 copies of ch14 (normal) but 3 copies of ch21 (Down’s).

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15
Q
  1. What % of trisomy cases are usually due to
    - Non-disjunction
    - Robertsonian translocation
A

Non-disjunction = 95%

Robertsonian translocation = 4%

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16
Q
  1. On a karyotype how would a trisomy 21 due to NDJ differ from a trisomy 21 due to robertsonian translocation?
A

Trisomy 21 due to NDJ = Seen as extra ch21, so three ch21’s in total seen

Trisomy 21 due to Robertsonian Translocation = Ch 21’s are two (normal) , but there are 2 ch14 and one of them has an 21q arm on it. So technically 3 ch21’s

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17
Q
  1. Why is it very difficult to predict the outcomes of some translocations?
A

Only have approximate probability of producing possible gametes

18
Q
  1. What are some outcomes of unbalanced chromosomes?
A
  • Some unbalanced outcomes may lead to spontaneous abortion of embryo so early that it’s 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
19
Q
  1. What is Terminal Deletion?
A

a deletion that occurs towards the end of a chromosome - new telomere has to be added to survive

20
Q
  1. What is an Interstitial deletion?
A

A deletion in the middle (or just not the end ) of the chromosome

21
Q
  1. What are some syndromes associated with interstitial deletions?
A

Prader-Willi
DiGeorge Syndrome
Cri du chat

22
Q
  1. What is an “Inversion”?
A

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

23
Q
  1. What is a “Duplication”
A

A duplication is where you get a region of the chromosome repeated eg globin gene family

24
Q
  1. What is a “Ring Chromosome”?
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.

25
Q
  1. How often do deletions of genetic info occur?
A

1:7000 live births

26
Q
  1. We already know that a deletion might be terminal or interstitial , but it can also result in a region of monosomy- what are the consequences of this?
A

Haploinsufficiency of some genes

Monosomic region has phenotypic consequences

Phenotype is specific for size and place on deletion

27
Q
  1. What is Haploinsufficiency?
A

a model of dominant gene action in diploid organisms, in which a single copy of the standard (so-called wild-type) allele at a locus in heterozygous combination with a variant allele is insufficient to produce the standard phenotype.

28
Q
  1. How can we view gross deletions?
A

Gross deletions seen on metaphase spread on G-banded karyotype

29
Q
  1. What is Cri-du-chat aka 5p- syndrome?
A

Cri du chat syndrome , also known as 5p is a genetic condition present from birth caused by deletion of genetic material on the p arm of chromosome 5. Infants with this condition often have a high-pitched cry that sounds like that of a cat.

30
Q
  1. What is seen clinically in Cri-du-chat syndrome?
A

•Developmental delay, microcephaly (brain doesn’t develop properly – shorter than normal head).

31
Q
  1. What genomic technology would you use to see Cri-du-chat syndrome?
A

•Easier to see using FISH.

32
Q
  1. Why is it hard to spot microdeletions/duplications?
A
  • Many patients had no abnormality visible on metaphase spread
  • High resolution banding, FISH and now CGH showed ‘micro’ deletions
  • Only a few genes may be lost or gained – contiguous gene syndrome
33
Q
  1. For the following micro deletion syndromes list where the deletions occur:
    •Velocardiofacial (DiGeorge, Shprintzen)
    •Wolf-Hirschhorn
    •Williams
    •Smith-Magenis
    •Angelman (mat)
    •Prader-Willi
A
  • Velocardiofacial (DiGeorge, Shprintzen) = 22q11
  • Wolf-Hirschhorn = 4p16
  • Williams = 7q11
  • Smith-Magenis =17p11
  • Angelman (mat) =15q11-1
  • Prader-Willi = 15q11-13 (pat)
34
Q
  1. What is unequal crossing over?
A
  • Chromosomes mis-align and result in unequal crossing over.
  • Some chromosomes are expanded while others are shortened.
35
Q

LOBS

A

xx

36
Q

36.• Describe the major structural abnormalities and provide a couple of named examples

A

terminal deletion, interstitial deletion, duplication, inversion, ring formation, microdeletion, microduplication, e.g. Cri-du-chat, diGeorge syndrome

37
Q

37.• Explain what is meant by a reciprocal and a Robertsonian translocation

A

reciprocal translocation = the exchange of material between two non-homologous chromosomes; Robertsonian translocation = the exchange of material between two acrocentric chromosomes resulting in the loss of the p arms and the bringing together of the two q arms around a single centromere)

38
Q

38.• Explain how double strand breaks and non-homologous end joining can result in translocations

A

two chromosomes undergo a DSB and the NHEJ repair system incorrectly sticks together two different chromosomes)

39
Q

39.Describe the process by which a balanced carrier of a translocation can lead to an unbalanced offspring ?

A

trivalent or quadrivalent formation in meiosis I can result in gametes which partially disomic and partially nullisomic ultimately leading to zygotes which are partially trisomic and partially monosomic)

40
Q

40.• Explain how unequal crossing over can result in (micro)deletions and (micro)duplications

A

misalignment of homologous chromosomes in meiosis I and recombination leads to production of gametes which may have gained or lost regions of the chromosome

41
Q

41.• Explain how abnormal karyotypes may be detected using stained metaphase chromosomes, FISH and arrayCGH

A

large structural abnormalities can be seen with G-banding and FISH whilst microdeletions and microduplications can only be seen with arrayCGH – explain processes

Clinical Genetics (5 decks)

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