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BIOL312 Medical Genetics > Lecture 6: Chromosomal Disorders > Flashcards

Lecture 6: Chromosomal Disorders Flashcards

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1
Q

What is a karyotype?

A

The size ordered chromosomal complement

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2
Q

How is a karyotype prepared?

A
  1. culture white blood cells and stimulate their division
  2. add colcemid to arrest the cells in metaphase
  3. digest with trypsin and strain with Giemsa
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3
Q

What is G-banding?

A

The reproducible pattern within each chromosome and between individuals following Giemsa staining
(darker regions = heterochromatin = A-T rich regions)
(lighter regions = euchromatin = G-C rich regions)

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4
Q

How does G-banding allow chromosome differentiation?

A

Helps to distinguish between chromosomes of a similar size

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5
Q

How is chromosome structure described?

A

divided into Short arm (p) and long arm (q)
- the arms are divided into sections running away from the centromere
- sections can then be further divided into sub-sections when chromosomes stretched out.

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6
Q

What are the two types of variations in chromosome number?

A

Polyploidy (more than two complete sets of chromosomes)

Aneuploidy (vary in number at just one chromosome)

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7
Q

How can aneuploidy occur?

A

Nondisjunction during meiosis where some chromosomes fail to segregate to different cells during meiosis I or meiosis II resulting in some gametes with trisomy and some gametes with monosomy

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8
Q

True or false: individuals with polyploidy are viable?

A

False: when egg fertilised by two sperm this can result in triploidy, which results in poor survivial of a born foetus but often rarely develop full term (spontaneous abortion)

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9
Q

What are the only three viable aneuploidies in humans?

A

Three viable autosomal trisomies:
Trisomy 21 - Down Syndrome (survival to adulthood)
Trisomy 13 - Patau Syndrome
Trisomy 18 - Edward Syndrome

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10
Q

What are the only viable autosomal monosomies?

A

there are none

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11
Q

Give 3 characteristics of Down Syndrome

A
  1. wide skull, flattened at the back
  2. tongue may be furrowed and protruding
  3. “Simian” creases on palms of hands and soles of feet
  4. epicanthic fold above the eyes
  5. Brushfield spots on the iris
  6. physical and mental retardation
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12
Q

What may individuals with Down Syndrome have increased likelihood of?

A

Congential heart defects
Leukaemia
Alzheimer’s disease

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13
Q

What are 3 characteristics of Patau Syndrome?

A
  1. severe cleft lip and palate
  2. physical and mental retardation
  3. defects in multiple organ systems
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14
Q

True or false: most people with Patau Syndrome survive into adulthood?

A

False: most die within the first year

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15
Q

What are 3 characteristics of Edward syndrome?

A
  1. Clenched fist
  2. rocker bottom feet (extended heel and flat sole)
  3. heart, kidney and other internal abnormalities
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16
Q

How long may individuals with Edward syndrome survive?

A

around 5-15 days

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17
Q

what is the frequency of the three viable trisomies (1 in _ live births)?

A

Down syndrome: ~ 1 in 700
Patau Syndrome: ~ 1 in 20,000
Edward Syndrome: ~ 1 in 6000

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18
Q

How many sex chromosome aneuploidies are there and what are they?

A

There are 4:
XO = Turner Syndrome
XXY = Klinfelter Syndrome
XXX = Metafemale
XYY

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19
Q

True or false: autosomal aneuploidies are more common in live births than sex chromosome aneuploidies?

A

False (and individuals with sex chromosome aneuploidies have greater survival into adulthood)

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20
Q

What are 3 characteristics of Turner syndrome?

A
  1. poorly developed secondary sexual characteristics
  2. Short stature
  3. Broad chest
  4. Webbed neck
  5. puffy hands and feet at birth
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21
Q

Are individuals with turner syndrome fertile (why/why not?)

A

no because they have low oestrogen during development so ovaries don’t develop properly (individual has rudimentary ovaries)

22
Q

What are 3 characteristics of Klinfelter syndrome?

A
  1. Breast development
  2. Female distribution of fat and public hair
  3. decrease in male characteristics
  4. small and underdeveloped testes so low fertility
  5. male genitalia
23
Q

What type of chromosomal abnormality is more common than aneuploidies?

A

chromosome rearrangement

24
Q

What are the different types genetic changes that can result from chromosomal rearrangements?

A

Deletions
Duplications
Inversions
Non-reciprocal translocations
Reciprocal translocations

25
Q

What is the difference between reciprocal and non-reciprocal translocations?

A

Reciprocal and non-reciprocal translocations occur between non-homologous chromosomes but in reciprocal translocations, the genetic material is swapped between two non-homologous chromosomes and in non-reciprocal translocations, genetic material moves from one non-homologous chromosome to another

26
Q

Give 3 congenital disorders associated with chromosome deletions
(6 are listed)

A
  1. Cri-du-chat syndrome
  2. Prader Willi Syndrome
  3. Angelman Syndrome
  4. Wolf-Hirschhorn syndrome
  5. Miller-Dieker syndrome
  6. Di George syndrome
27
Q

What are three characteristics of Cri-du-chat syndrome?

A
  1. Babies have cat-like cry due to defects in glottis and larynx
  2. Wide face with saddle nose
  3. Physical and mental retardation
28
Q

What is the chromosome deletion that causes Cri-du-chat syndrome?

A

5p15 (deletion in short arm of chromosome 5)

29
Q

Can individuals with Cri-du-chat syndrome pass on the disorder to their offspring?

A

In theory yes because they have normal puberty and are fertile but most die before reaching child-bearing age.

30
Q

What causes chromosomal rearrangements?

A

crossing-over between regions of repetitive DNA during meiosis

31
Q

What are the resulting chromosomal rearrangements resulting from crossing over of repetitive DNA that is:
1. a direct/in line repeat
(A) on same chromosome
(B) on non-homologous
chromosome
2. inverted repeat

A
  1. Direct/in line repeat sequences:
    (A) on same chromosome = repeat sequences may align and form a loop, crossing over results in loss of the loop and thus a DELETION
    (B) on non-homologous chromosome = repeat sequence may align and cross over resulting in a RECIPROCAL TRANSLOCATION
    or repeat sequences may line up out of register and crossing over results in a DELETION in one chromosome and a DUPLICATION in the other
  2. inverted repeats may form a hairpin loop and crossing over results in INVERSIONS
32
Q

What is a balanced translocation?

A

When a translocation that occurs during meiosis results in the same doses of genes in the gametes as normal

33
Q

How can unbalanced translocations occur?

A

During meiosis, 4 non-homologous chromosomes can come together in a tetravalent that undergo crossing over.
- this can result in a mixture of both balanced and unbalanced translocations being present in the subsequent gametes

34
Q

What may be done if a spontaneous abortion was found to have an unbalanced translocation?

A

Check the parents to see if they have this re-arrangement because, if they do, it may affect future offspring

35
Q

True or false: chromosomal translocations can be inherited? why/why not?

A

True: if the translocation is balanced the individual has the normal number of genes so may not be aware they even have a translocation

36
Q

How to microdeletions occur?

A

Occur spontaneously because of recombination between repeated sequences such as transposable elements

37
Q

What are the advantages and disadvantages of diagnosing chromosomal disorders by Giemsa-stained karyotyping?

A

Advantages: good for aneuploidies and large deletions/duplications that can be identified at a gross level.

Disadvantages: cant detect small rearrangements and is time consuming

38
Q

What are the alternative methods of diagnosing chromosomal disorders when karyotyping fails? (4 answers)

A
  • FISH
  • Array competitive genomic hybridisation (Array CGH)
  • Single nucleotide polymorphism (SNP) profiling
  • Whole genome sequencing
39
Q

How does FISH work in the diagnosis of chromosomal disorders?

A
  • spread chromosomes on slide (full karyotype ideally)
  • denature DNA in situ on slide
  • hybridise with fluorescently labelled oligonucleotide probes corresponding with region of interest
  • wash off unbound probe
  • stain DNA with DAPI fluorescent dye
  • observe under fluorescent microscope
    (do same for unaffected region of same chromosome using a different colour fluorescence)
40
Q

What is the advantage of using interphase FISH to diagnose chromosomal disorders?

A

there is no need to culture the cells

41
Q

What oligonucleotide probes are commonly used when screening for trisomies?

A

commonly use probes for chromosome 13,18,21, X and Y

42
Q

What are the limitations of FISH?

A
  • small deletions/duplications cannot be detected
  • can only test region corresponding to the probe used so prior knowledge is needed to design the complementary probe
43
Q

Why might a chromosomal disorder be suspected over a single gene disorder?

A

chromosomal disorders tend to affect multiple genes resulting in multi-system effects

44
Q

How is an array CGH set up and analysed?

A
  • microarray consisting of thousands of short DA sequences spanning the entire genome
  • DNA from the patient and control is extracted and labelled with different fluorescent dyes
  • DNA is mixed together in equal quantities and hybridised to the slide
  • unbound DNA is washed off
  • Slide scanned
45
Q

How is an array CGH interpreted and used to diagnose chromosomal disorders?

A
  • since the patient and control DNA is mixed in equal quantities, most spots of the microarray will have equal fluorescence of the two colours
  • the graph is plotted showing the ratio of patient to control fluorescence
  • peak in graph means there is more patient than control DNA at this location = DUPLICATION
  • drop in graph means there is less patient DNA than control at this location = DELETION
46
Q

How is a SNP array set up and analysed?

  • read up about how these are set up as i am confused but need to move on for now………………………………………………………………………………………….
A
  • Microarray consisting of thousands of oligonucleotide pairs spanning the genome
  • Each oligonucleotide pair/variant differs at a single base pair
  • ## Hybridise with fluorescently labelled DNA from the patient
47
Q

How are SNP arrays interpreted to diagnose chromosomal disorders?

A

If patient is homozygous, there will be full intensity of fluorescence at this spot.

If patient heterozygous, there will be reduced but equal intensity of fluorescence at both spots

If patient has deletion of one allele, there will be no fluorescence at the spot where the deletion is/reduce fluorescence at the spot where the deletion is not.

If patient has deletion of both alleles, there will be no signals in those spots.

If patient has duplication, there will be increased intensity of fluorescence in the corresponding spots

48
Q

What is the expected intensity of fluorescence in a typical individual in SNP array profiling?

A

2 doses (either homozygous or heterozygous)
- if only one dose of fluorescence is detected this indicates a deletion within a SNP region

49
Q

SNP arrays are (1) and more frequently used than aCGH?

A

(1) Cheaper

50
Q

What is non-invasive pre-natal diagnosis/testing (NIPT/NIPD)?

A
  • free foetal DNA in maternal serum amplified and sequenced by NGS
  • high depth sequence reads used to measure chromosome number (e.g. if there are more sequence reads for one chromosome above the average compared to the number of reads for other chromosomes, this indicates aneuploidy)
51
Q

What can be detected using NIPT/NIPD?

A

aneuploidies, sex of foetus, and some single gene mutations.

52
Q

What chromosomal disorder is NIPT often offered for?

A

Down Syndrome (any difference in read depth between the chromosome 21 fragments and those from other chromosomes can be indicative of trisomy 21)

BIOL312 Medical Genetics (10 decks)

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