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Genetic Counseling Boards > Cytogenetics > Flashcards

Cytogenetics Flashcards

1
Q

History of Cytogenetics

A
  • “Dark Ages”: before 1952; chromosomes visualized by number in humans unknown
  • “Hypotonic Period”: 1952-1959; # chromosomes identified in 1956, DS/TS/KS discovered in 1959, karyotyping popular
  • “Banding Era”: 1974-1989; Giemsa staining used and chromosomes identified based on banding pattern
  • “Molecular Era”: 1989-present; FISH, CGH, array CGH used
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2
Q

Number of Genes in a Chromosome

A

500-4,000

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3
Q

Number of Genes in a Metaphase Band

A

50-100

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4
Q

Number of Genes in a High-Res Prophase Band

A

50

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5
Q

General Phenotype of Chromosomal Abnormality

A

developmental delays, dysmorphology, birth defects, other medical problems

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6
Q

Chromosomal Dosage

A

more imbalance present worse problems are; extra dosages much better tolerated than missing ones

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7
Q

What percentage of all spontaneous 1st trimester abortions have a chromosomal condition?

A

50%

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8
Q

What percentage of all live births have a chromosomal condition?

A

1%

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9
Q

What is the most common aneuploidy resulting in live birth?

A

T21

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10
Q

What is the most common aneuploidy in 1st trimester SAbs?

A

T16

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11
Q

What percentage of pregnancies in women >35yrs have a chromosomal condition?

A

2%

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12
Q

Indications for Testing Chromosomes

A
  • problems in early growth/development
  • stillbirth and neonatal death
  • fertility problems
  • family history suspicious of chromosomal abnormality
  • AMA/abnormal prenatal screen
  • neoplasms
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13
Q

Anatomy of a Chromosome

A
  • comprised of two sister chromatids
  • centromere
  • telomeres
  • p arm (short)
  • q arm (long)
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14
Q

Chromosomal Shapes

A
  • defined by location of centromere
  • metacentric
  • submetacentric
  • acrocentric
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15
Q

Group A Chromosomes

A

1, 2, 3

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16
Q

Group B Chromosomes

A

4, 5

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17
Q

Group C Chromosomes

A

6, 7, 8, 9, 10, 11, 12, X

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18
Q

Group D Chromosomes

A

13, 14, 15

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19
Q

Group E Chromosomes

A

16, 17, 18

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20
Q

Group F Chromosomes

A

19, 20

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21
Q

Group G Chromosomes

A

21, 22, Y

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22
Q

Metacentric Chromosomes

A

Groups A and F (1, 2, 3, 19, 20)

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23
Q

Submetacentric Chromosomes

A

Groups B, C, E (4, 5, 6, 7, 8, 9, 10, 11, 12, X, 16, 17, 18)

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24
Q

Acrocentric Chromosomes

A

Groups D and G (13, 14, 15, 21, 22, Y)

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25
Q

Giemsa Bands

A

400-500

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26
Q

High-Res Prophase Bands

A

800-1200

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27
Q

Dark Giemsa Bands

A

more condensed, less transcriptionally active, late replicating, AT rich, heterochromatin

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28
Q

Light Giemsa Bands

A

more transcriptionally active, CG rich, euchromatin

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29
Q

C-banding

A
  • selectively stains heterochromatin around centromere
  • inherited polymorphisms of 1, 9, 16, and Yq make it look like there’s more material
  • identifies dicentric chromosomes
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30
Q

Silver Staining

A

detects NORs present at end of acrocentric chromosomes, which contain rRNA genes

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31
Q

Karyotyping Methodology

A
  • Blood sample drawn
    (WBCs, skin, amniocytes, chorionic villi, umbilical cord blood can also be used)
  • RBCs separated out and WBCs stimulated to divide with phytohemagluttinin (PHA)
  • WBCs cultured and incubated for 3 days
  • Colchicine added to destroy spindle fibers and arrest cell in metaphase
  • WBCs separated off and hypotonic solution added
  • Cells fixed and dropped onto slide
  • Slide is stained with banding solution and photographed (from photographed chromosome spread, karyotype generated by cutting out chromosomes and arranging them by classification)
  • Look at ~20 cells and takes a week to finish (if mosaicism is suspected, more cells need to be looked at (50-100))
32
Q

Band Nomenclature

A
  • arms divided into p and q
  • q10 and p10 = centromeres
  • each arm separated into regions (1-n) starting from centromere to telomere
  • each region separated into bands starting with landmark band closest to centromere (1-n)
  • band further divided into sub-bands (represented by a decimal)
  • telomere referred to as qter/pter
  • Example: 6p23 -> short arm of chr 6, region 2, band 3
33
Q

ISHC Karyotype Nomenclature

A
  • cen = centromere
  • del = deletion
  • der = derivative chromosome
  • dup = duplication
  • inv = inversion
  • mar = marker chromosome
  • mat = maternal origin
  • pat = paternal origin
  • t = translocation
  • ter = end of chromosome arm
    • = gain of material
    • = loss of material
  • / = mosaic
34
Q

When to Order Karyotype

A
  • patients with obvious chromosomal syndromes
  • family history of chromosomal rearrangements
  • history of multiple miscarriages
  • prenatal diagnosis of aneuploidy
35
Q

FISH Methodology

A
  • DNA probe prepared that is fluorescently labeled and complementary to target region
  • chromosome denatured and exposed to probe, which attaches to complementary sequence
  • slide examined under fluorescent lighting (presence of signal indicates probe attachment; lack of signal indicates missing target sequence)
  • results available within 48 hours
  • if abnormal, needs to be followed up with karyotype or microarray
36
Q

When is FISH Used

A
  • rapid diagnosis of aneuploidy (T13/18/21, X, Y)
  • rapid diagnosis of triploidy
  • specific microdeletions syndromes via locus-specific probes
  • specific duplications
  • identification of translocations/marker chromosomes
37
Q

Limitations of FISH

A
  • need to know chromosomal region of interest
  • probe may hybridize even if there is a small change in region of interest; appears as though nothing is wrong
  • does not distinguish trisomy due to aneuploidy vs chromosome rearrangement
  • not efficient for genome-wide analysis
38
Q

Limitations of Karyotype

A
  • resolution limited to large structural differences >5Mb; cannot detect small deletions/duplications/insertions/point mutations
  • may not be able to identify marker chromosomes or other small structural rearrangements
  • may be unable to tell if rearrangement is truly balanced or not
  • unable to detect UPD, ROH
39
Q

Array CGH Methodology

A
  • patient and control DNA labeled with fluorescent dyes and applied to microarray
  • patient and control DNA compete to attach to probes
  • microarray scanner measures fluorescent signals
  • computer software analyzes data and generates plot
  • if patient DNA > control DNA, duplication
  • if control DNA > patient DNA, deletion
  • if no del/dup, patient and control DNA hybridize equally
40
Q

Array CGH Limitations

A
  • cannot detect balanced rearrangements
  • VUSs possible
  • probe spacing (where in genome) vs probe resolution (how small to detect); if large probe used, may not be able to detect small deletions
  • may not detect low-level mosaicism (<20%)
  • cannot detect triploidy or ROH/UPD
41
Q

SNP Array Methodology

A
  • looks at variation in nucleotide bases of patient DNA vs database/reference DNA
  • detects SNPs in heterozygous (AB) and homzygous states (AA, BB)
  • detects number of alleles present
  • able to detect ROH, UPD, copy neutral variations, triploidy
42
Q

SNP Array Limitations

A
  • unable to detect balanced rearrangements
  • potential VUSs
  • may not detect low-level mosaicism (<20%)
43
Q

Chromosomal Duplications

A
  • section of chromosome has made extra copy of itself
  • direct = tandem duplication
  • inverted = mirror duplication
44
Q

Chromosomal Deletions

A
  • loss of genetic material
  • interstitial = in the middle of chromosome
  • terminal = at end of chromosome
45
Q

Chromosomal Insertions

A
  • piece of one chromosome inserted into completely different chromosome
  • results from at least three breaks in two chromosomes
46
Q

Chromosomal Inversions

A
  • chromosome breaks in two places and piece reinserts itself in opposite orientation
47
Q

Pericentric inversions

A
  • involve centromere
  • may produce chromosomally unbalanced gametes resulting from recombination
  • homologues form inversion loop during meiosis
  • crossover leads to 4 possible gametes: normal homologue, inverted homologue, homologue with p arm dup and q arm del, homologue with p arm del and q arm dup
  • only heterozygotes with small distal (non-inverted) segments will have viable abnormal offspring
48
Q

Genetic Counseling Points for Pericentric Inversions

A
  • risk of having abnormal child after having a recombinant child is 5-15%
  • risk of having abnormal child w/o fhx of recombinant child is 1%
  • actual risks depend on specific inversion
  • prenatal diagnosis offered to any heterozygotes whose family had a recombinant child; any heterozygote with specific inversions; any heterozygotes with inversions involving chr13/18/21; molecular analysis to exclude deletion in PWS/AS region of 15q11-13
49
Q

Paracentric Inversions

A
  • do not involve centromere
  • theoretically cannot produce unbalanced offpsring
  • recombinant gametes formed are acentric or dicentric, both of which are nonviable
50
Q

Genetic Counseling Points for Paracentric Inversions

A
  • hard to detect on classic karyotype; need at least high-res prophase banding
  • risk of abnormal offpsring is 0.1-0.5%
  • prenatal diagnosis may not be offered except when parent carries inversion shown in literature to result in abnormal offspring
51
Q

Isochromosomes

A
  • chromosome breaks at centromere and kinetochore micotubules separate short and long arms as opposed to separating chromatids
  • complete duplication of p arm or q arm
  • ISOp or ISOq
52
Q

Reciprocal Translocations

A
  • two different chromosomes exchange segments with each other, typically between non-homologous chromosomes
  • generates atypical derivative chromosomes
  • translocated segments and centric segments
  • chromosome number indicated by which centromere it contains
  • balanced translocations have no loss or gain of genetic material
53
Q

Single-Segment Exchange

A
  • one of translocated segments is very small and comprises only telomeric region of chromosome
  • more likely to result in live-born child with problems
54
Q

Double-Segment Exchange

A
  • both translocated segments are large
55
Q

Alternate Segregation

A
  • 2:2
  • A&B; A’&B’
  • only way to get phenotypically normal offspring
  • assume that this is frequent
56
Q

Adjacent-1 Segregation

A
  • 2:2
  • A&B’; A’&B
  • segregation involves different centromeres
  • more common
  • most likely when translocated segments are small
57
Q

Adjacent-2 Segregation

A
  • 2:2
  • A&A’, B&B’
  • segregation involves same centromeres
  • rarer and less likely to result in liveborn child
  • most likely when centric segments are small
58
Q

Tertiary Segregation

A
  • 3:1
  • most likely when quadrivalent is lop-sided
  • 2 of 3 chromosomes are normal
59
Q

Interchange Segregation

A
  • 3:1
  • most likely when quadrivalent is lop-sided
  • 2 of 3 chromosomes are derivative
60
Q

4:0 Segregation

A
  • all four chromosomes go to one cell
  • most likely when translocated and centric segments are both large
  • not viable
61
Q

Genetic Counseling Points for Reciprocal Translocations

A
  • a little bit of monosomy but more of trisomy means there’s less imbalance and less material rearranged but more likely to have baby with problems
  • the larger the segments involved, may continue to have miscarriages but less likely to bring a baby with problems to term
  • liveborn aneuploid offspring demonstrates viability for that abnormal combination to recur (recurrence risks high)
  • ascertainment by miscarriage or infertility is more difficult to predict
62
Q

Four Factors Determining Magnitude of Risk (Reciprocal Translocations)

A
  • mode of ascertainment (presence of liveborn with problems or miscarriages)
  • predicted type of segregation leading to potential viable gametes
  • Sex of transmitting parent (risk always high if from mother than from father; selection process against abnormal sperm; whatever egg is ovulated, whether normal or not, is the one that’s available)
  • the assessed imbalance of the potentially viable gamete (risks range from 0% to 30% and depend on actual cytogenetic imbalance)
63
Q

Frequency of Autosomal Translocation Carriers

A

1/500

64
Q

Robertsonian Translocations

A
  • translocations involving chr 13, 14, 15, 21, 22, Y
  • typically results in loss of NORs
  • balanced carriers have 45 chromosomes
65
Q

Frequency of Robertsonian Translocation Carriers

A

1/1000

66
Q

Three Mechanisms for Robertsonian Translocations

A
  • centric fusion: part of centromere from one chromosome and part from other join together
  • union following breakage in one short arm and one long arm
  • union following breakage in both short arms (dicentric chromosomes; more common)
67
Q

Alternate Segregation (RT)

A
  • 2:1
  • produces normal and balanced gametes
  • favored in male and female carriers
  • females have 20% risk to have abnormal offspring
68
Q

Adjacent Segregation (RT)

A
  • 2:1

- produces two types of disomic and nullisomic gametes

69
Q

Segregation of Homologous Robertsonian Translocations

A
  • no gametes are balanced
  • 1:0 segregation lead to disomic or nullisomic gamete
  • 100% chance for abnormal offspring, 0% chance for normal offspring
  • only T13 or T21 viable
70
Q

Genetic Counseling Points for Robertsonian Translocations

A
  • only balanced conceptuses with T13 or T21 survive
  • fetal T14/15/22 miscarry
  • translocations involving chr 14/15 have concerns for UPD
  • if child has der(21) due to rob (21q;21q) and a normal sib, translocation is de novo
71
Q

Empiric Risks for Robertsonian Translocations

A

Chance for Unbalanced Offspring:

13;13 - 100% mother, 100% father

13;14 - 1% mother, 1% father

13;15 - 1% mother, 1% father

13;21 - 15% mother, 1% father

13;22 - 1% mother, 1% father

14;21 - 15% (amnio)/10% (liveborn) mother, 1% father

15;21 - 10% mother, 1% father

21;21 - 100% mother, 100% father

21;22 - 10% (liveborn) mother, 1% father

14;15, 14;22, 15;22 lethal in utero

72
Q

3:0 Segregation (RT)

A

rare

73
Q

Y-Chromosome Rearrangements

A
  • Inversions: not usually clinically significant
  • Translocations: 70% of the time, the other chromosome involved is acrocentric (chr 15, 22) w/o gain/loss of euchromatin and normal fertility; reciprocal exchange between Yq and autosome typically de novo, leads to balanced male, infertility
74
Q

X-Chromosome Rearrangements

A
  • relative tolerance for X chromosome abnormalities compared to autosomes d/t X-inactivation
  • Inversions: breakpoints in X critical region may influence female phenotype; inheritance of recombinant X leads to variant form of Turner syndrome (del(Xq)/dup(Xp) characterized by normal/tall stature and ovarian dysgenesis; del(Xp)/dup(Xq) associated with short stature and intact ovarian function); recombinant X in males is lethal in utero; paracentric inversions typically don’t have phenotypic consequence unless breakpoints in critical region
  • Translocations: when there are X;autosome translocations, normal X is preferentially inactivated; in unbalanced offspring, der(x) preferentially inactivated; adjacent-1 segregation results in functional X disomy or X deletion as well as autosomal deletion or duplication; 3:1 segregation results in tertiary trisomy -> risk of X duplication, X duplication/autosome duplication or tertiary monosomy -> risk of X deletion/autosome deletion; adjacent-2 segregation results in X deletion/autosome duplication or X duplication/autosome deletion; 50% females carriers and all male carriers infertile; fertile females at risk of having offspring with Turner/Klinefelter variants
75
Q

Common Inversions (no phenotypic effect)

A
  • inv(2)(p11.2q13)
  • inv(Y)(p11q13)
  • inversions of 1, 9, 16, and Y heterochromatin

Genetic Counseling Boards (22 decks)

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