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1PATH3305 Medical Genetics > Lecture 11: Introduction to Cytogenomics > Flashcards

Lecture 11: Introduction to Cytogenomics Flashcards

1
Q

What does Medical Cytogenomics STUDY? INVESTIGATES? EMPLOYS?

A
  • Studies GROSS HUMAN GENOME VARIATION IN HEALTH AND DISEASE
  • Investigates HEREDITY AT THE CELLULAR LEVEL
  • Employs VARIETY OF METHODS REQUIRING HIGHLY SPECIALISED SKILLS
    highly specialised skills
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2
Q

What are Human Chromosomes? =4

A
    • Cellular structures
    • Compacted DNA (1 DNA molecule = 1 chromosome)
    • DNA-protein interactions
      – ‘compaction’
      – ‘regulation of gene expression’

4.* Ensure CORRECT CELLULAR INHERITANCE’ VIA CELL DIVISION

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3
Q

CELL DIVISION

A

MITOSIS AND MEIOSIS

UNDERTSAND PROCESSES

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4
Q

Human diploid chromosome set?

KARYOGRAM =?

A

1 - #22 – autosomes;

Karyogram - ordered image of the chromosomes from a single cell..
on metaphase spread

X , Y – sex chromosomes

22 + sex chr = 23

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5
Q

Metaphase chromosome morphology

A

‘p’ arm (short) =2
‘q’ arm (long) = 2

telomere at each end
- hence 4 on each arm
- CENTROMERE in middle
—-

…LOCATION OF CENROMERES…

Metacentric - in middle

Submetacentric - above middle
Acrocentric - near top of both chr
= will have ‘satellite’ and ‘stalk’ …above the acrocentric line

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6
Q

Selected methods for cytogenomic analysis: 5

A
  1. Conventional cytogenetics
  2. chromosomal microarray
  3. quantitative fluroescence -PCR (QF-PCR)
  4. Genomic sequencing
  5. FISH - Fluorescence IN SITU HYBRIDIASTION
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7
Q

Selected methods for cytogenomic analysis: Conventional cytogenetics = 2

A
  1. requires dividing cells
  2. resolution 5-10Mb
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8
Q

Selected methods for cytogenomic analysis:

chromsomal array- 2

A
  1. DNA - based
  2. Resolution approx 50Kb
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9
Q

Selected methods for cytogenomic analysis:

Quantitative Fluorescence – PCR (QF-PCR)

A
  • DNA - based
  • Resolution single locus
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10
Q

Selected methods for cytogenomic analysis:

‘Fluorescence in situ hybridisation (FISH)’

A
  • Dividing/non-dividing cells
  • Resolution ~200Kb
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11
Q

Selected methods for cytogenomic analysis:

‘Genomic sequencing’

A
  • DNA - based
  • Resolution single locus
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12
Q

what are chromosomal abnormalities?

types?

A

Deviations from the standard pattern
of 23 pairs of chromosomes with known morphology

types:
–Numerical abnormalities
–Structural abnormalities

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13
Q

What is ‘Numerical chromosome abnormalities’
= 2

A
  • Deviations in chromosome number
  • Usually occur de novo – low recurrence risk
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14
Q

example of ‘Numerical chromosome abnormalities’

A
  • Down syndrome
  • Prevalence ~ 1:1000 births
    (Roizen N & Patterson D, 2003 Lancet 361:1281-1289)
  • Additional copy of chromosome 21 (trisomy 21)
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15
Q

Mechanisms of numerical chromosome abnormalities = 2

A
  1. cell division errors
  2. fertilisation errors
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16
Q

Mechanisms of numerical chromosome abnormalities: ‘CELL DIVISION ERRORS’

= 4

A
  1. Checkpoint defects
  2. cohesion defects
  3. centrosome amplification
  4. microtubule defects

‘diagram on slide 11’

17
Q

Mechanisms of numerical chromosome abnormalities:

‘FERTILISATION ERRORS’

A

Example
- ovum = 23, X

  • 2 SPERM ON IT
  • 23, Y AND 23 X

HENCE = DISPERMY

18
Q

Euploid numerical abnormalities means =
examples -2

A

Euploid numerical abnormalities means =
‘(multiples of the haploid set)’

  1. TRIPLOID = 3 Sets of chromosomes for each order
  2. TETRAPLOID = 4 sets of chromosomes for each order
19
Q

Aneuploid numerical abnormalities means?

examples? - 2

A

Aneuploid numerical abnormalities means
‘(gain or loss of one or a few chromosomes)’

  1. TRSIOMY 21 (3 chromosomes for order 21)
  2. Monosomy X (X or Y missing only one sex chro = (X, …)
20
Q

Structural chromosome abnormalities?

MECHANISIM?
TYPES?
INHERITANCE?

A
  • ‘Mechanism: chromosomal breakage and reunion
    in a different configuration’

TYPES
* Balanced – no net gain or loss
* Unbalanced –gain/loss of chromosomal material

  • May be inherited –’ high recurrence risk’
21
Q

Balanced structural abnormalities:

A

Balanced structural abnormalities:
‘Robertsonian translocations’

Translocation (14;21)
NOTE: 45 chromosomes

22
Q

Risk for chromosomally abnormal offspring…

A

(14, 14 and 21, 21) + ‘balanced translocation’ (14, t14;21, 21)

= 14, 14;21 and 21,21
UNBALANCED TRANSLOCATION (TRANSLOCATION TRISOMY 21)

DIAGRAM ON SLIDE 16

23
Q

Other balanced rearrangements:
‘reciprocal translocations’

A

Other ‘balanced’ rearrangements:
‘reciprocal translocations’
=

Translocation of (11;22)

der(11) and der(22)

Meiosis I pairing

diagram on slide 17

24
Q

Balanced structural rearrangements challenging
for detection = 2

A
  1. INSERTION
    (“cut and paste”)
  2. INVERSION
    (‘FLIP’)
    - Paracentric (near above)
    - Pericentric (near below)
25
Q

Unbalanced structural abnormalities 1

A
  1. chr 13 pair
    NO ABNORMALITY
  2. CAN LEAD TO
    – DELETION
    of chr 13 …OF TERMINAL SEGMENT

—DUPLICATION
of genes on chr 13 ..becomes longer

  1. INTERSTITIAL DELETION on chr 16

LOOK AT DIAGRAM ON SLIDE 19

26
Q

Unbalanced structural abnormalities 2 =

A
  1. Sister chromatid recombination
  2. loss of both termini
  3. ring chromosome (x)
  4. Isochromosome (x)
  5. Marker chromosomes (unknown origin)
27
Q

define :
Mosaicism

A

Presence of ‘cell lines’ with ‘different chromosomal
constitution’ in the ‘same individual’ – ‘numerical or
structural changes’

28
Q

Clinical impact of cytogenomic variants = 3

A

1 * No apparent effect

2 * Reproductive issues

3 * Apparent clinical concerns
– Ambiguous genitalia
– Multiple congenital anomalies
– Neuro-developmental issues
– Cancer

29
Q

Clinical impact of cytogenomic variants:

‘Apparent clinical concerns’ =4

A

1 – Ambiguous genitalia

2 – Multiple congenital anomalies

3 – Neuro-developmental issues

4 – Cancer

30
Q

A major proportion of chromosomal abnormalities are ‘detected prenatally’

A

TABLE ON SLIDE 23

31
Q

‘Maternal age’ and risk of chromosomal
abnormality

A

Maternal age and risk of chromosomal
abnormality = PROPORTIONAL

HIGHER AGE = HIGHER RISK OF CHROMOSOMAL ABNORMALITY IN INFANTS

EXAMPLE ON GRAPH WAS ON TRISOMY 21
…Risk increased from age 35/36 ish (frequency = 0.1 ish or less)
- great at 45 approx frequency of 0.10

32
Q

Subject of human cytogenomics?

mechanisms?

recurrence risk?

clinical impact?

A
  1. Chromosome variation in health and disease is a subject of human cytogenomics
    • Different mechanisms underlying
      chromosomal aberrations

3 * Different recurrence risk associated with
numerical and structural chromosomal
anomalies

4 * Different clinical impact of chromosomal
abnormalities

1PATH3305 Medical Genetics (20 decks)

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