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Board Review 2024 > Cytogenetics > Flashcards

Cytogenetics Flashcards

1
Q

Abbreviation: add

A

additional material of unknown origin

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2
Q

Abbreviation: cht

A

chromatid

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3
Q

Abbreviation: der

A

derivative chromosome

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4
Q

Abbreviation: dic

A

dicentric chromosome

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5
Q

Abbreviation: dn

A

de novo

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6
Q

Abbreviation: fra

A

fragile site

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7
Q

Abbreviation: h

A

heterochromatin

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8
Q

Abbreviation: i

A

isochrom

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9
Q

Abbreviation: dir ins

A

direct insertion

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10
Q

Abbreviation: inv ins

A

inverted insertion

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11
Q

Abbreviation: ish

A

in situ hybridization

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12
Q

Abbreviation: mar

A

marker chromosome

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13
Q

Abbreviation: rcp

A

reciprocal translocation

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14
Q

Abbreviation rea

A

rearrangement

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15
Q

Describe what the following karyotype means: 46, XX, 9qh+

A

normal female, additional heterochromatic material in the long arm of chrom 9

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16
Q

Describe what the following karyotype means: 47, XXY/46,XY

A

Mosaic KS

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17
Q

Describe what the following karyotype means: 47,XX, +8/46,XX

A

Mosaic T8

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18
Q

Describe what the following karyotype means: 92,XXXX

A

Tetraploidy

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19
Q

Describe what the following karyotype means: 46,XX,del(5)(p13)

A

deletion on the short arm of chromosome 5

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20
Q

What are some indications for which you would want to do chromosome analysis

A
  1. 2 or more major malformations
  2. 1 major malformation in the presence of minor anomalies
  3. specific chromosome syndrome suspected
  4. ID and dysmorphic features
  5. ambiguous/abnormal genitalia
  6. female with short stature
  7. offspring of a parent with a balanced t (and vice versa)
  8. recurrent abnormalities and infertility
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21
Q

What is the best mitotic stage to observe/chromosomes and why

A

metaphase bc the chroms are the shortest and most compact

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22
Q

During a chromosome analysis, what are the bare minimum requirements to get a good sample/result

A

look @20 metaphase spreads: gives a 14% chance of not ruling out mosaicism (86% chance of ruling out mosaicism; with 50 metaphases, the chance of not ruling out mosaicism decreases to 6%)
a minimum of 5 karyotypes are examined

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23
Q

What is a marker chromosome

A

structurally abnormal chromosome that you cannot identify (contains genetic material but is NOT a chromosome, can look like a floating dot on chromosome spread)

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24
Q

what are the acrocentric chromosomes

A

13, 14, 15, 21, 22

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25
Q

How are chromosomes classified

A

dependent on the size of the chromosome, banding pattern, and position of the centromere
p=short arm, q=long arm

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26
Q

Define metacentric

A

centromere in the middle of the chromosome, equal amts of genetic material on each side ex:chrom 1

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27
Q

Define submetacentric

A

centromere off-centered, less material on the p arm, more material on the q arm

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28
Q

Define acrocentric

A

centromere at the top of the chromosome, virtually not material on the short arm (only satellite material- for ribosomal RNA production)
chrms 13, 14, 15, 21, 22

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29
Q

What is chromosome resolution? What are the ideals for amnio/blood and bone marrow

A

can only visualize gains, loses, and rearrangements in chroms
chromosome stretches and more bands= greater resolution (but have more overlap, harder to visualize)
@ 850 level, 1 band =50-100 genes
ideal resolution for blood/amnio is 550 resolution; ideal for bone marrow is 400

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30
Q

Describe what the following karyotype means: 45,X,t(2;4)(p11;q13), t(7;21)(p13;q12)

A

45,X, with a translocation of p11 on chromosome 2 to chromosome 4 and a translocation of q13 from chromosome 4 to chromosome 2
AND another translocation of p13 from chromosome 7 to chromosome 21 and a translocation of q12 from chromosome 21 to chromosome 7

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31
Q

How does FISH technology work

A

use of fluorescent molecules (labeled DNA probes) to detect a particular chromosome, gene, or chromosome region with a specific complementary sequence visualized with fluorescent microscope
if a probe lights up, the gene is present; if nothing lights up, the gene is not present
MUST BE LOOKING FOR A SPECIFIC ABNORMALITY ON THE CHROMOSOME
can get resolution as great as 2-5 genes/probe, but probe needs to be highly specific

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32
Q

Define clones in terms of cancer

A

a cell population derived from a single progenitor cell
needs to meet at least one of the following criteria:
at least 2 cells that have a gain
at least 2 cells with the same structural rearrangement (del, add, t)
at least 3 cells that have the same numerical aberration (much easier for a chromosome to be lost than gained)

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33
Q

What is interphase FISH and when is it used

A

looking at 200 interphase chroms in the nucleus, only can visualize exactly what you are probing for, don’t get any other info for the other chroms
used for cancer. ex:
Abl on chrom 9 and BCR on chrom 22 for chronic myelogenous leukemia, if they co-localize (in the form of a translocation), FISH will light yellow to indicate over lap of red and green probes

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34
Q

What is a microarray? What is it’s resolution

A

measures gains and losses of DNA, can visualize up to 2.5mil bp (~15-30 genes) but usually need a minimum of 5 million bp
use for microdels, CNVs, but CANNOT DETECT BALANCED REARRANGEMENTS

better resolution than karyotype

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35
Q

What is a translocation

A

a two way exchange of material between 2 chroms. a break occurs in one arm of each chrom involved, breaks switch position

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36
Q

What is a balanced translocation

A

reciprocal, exchanges are equivalent, no loss of genetic material

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37
Q

What is an unbalanced translocation

A

partial trisomies and monosomies, loss or gain of some genetic material

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38
Q

What is a single segment exchange

A

one of the translocation segments is small (in the telomeric region) ex: t(1:4)(q44;q43.3)
may have no effect on phenotype or some effect

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39
Q

What is a double segment exchange

A

both translocated segments are large; translocations at breakpoints at or within a centromere exchanging entire arms are called whole arm translocations
individuals with balanced exchanges are phenotypically normal, problems arise when they try to reproduce

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40
Q

What are the 3 possible modes of segregation

A
  1. 2:2- 2 chromosomes to one cell, two chromosomes to the other (typical)
  2. 3:1- 3 chromosomes to one cell, one chromosome to the other
  3. 4:0- all 4 homologs go to one cell

method of segregation is dependent on the size of the translocated segments

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41
Q

Describe alternate segregation

A

one centromere goes to one pole, the next goes to the other pole (each centromere goes alternately to one or the other pole)
daughter cells are normal/balanced
only mode that leads to gametes with a complete genetic compliment (2:2 segregation)

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42
Q

Describe adjacent 1 segregation

A

unlike centromeres travel together (ONE is UNlike centromeres)
the most common form of malsegregation
ex: chromatin on the long arm of chrom 11 is translocated to the tip of chrom 3 on the short arm, while the telomeric tip of chrom 3 on the short arm has moved to chrom 11
gametes will be: partial 11q trisomy, partial 11q monosomy
(2:2 segregation)

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43
Q

Describe adjacent 2 segregation

A

like centromeres travel together
relatively uncommon
typically limited to t’s where each chrom has a short arm with little genetic content and can be viable in the trisomic state (most commonly involves 9p and a D or G chrom (D: 13, 14, 15; G: 21,22))
breakpoint usually between the upper long arm of one chrom and immediately below the centromere in the other chrom; the LEAST IMBALANCED, LEAST MONOSOMIC GAMETE WILL BE VIABLE
most cause a lethal imbalance during early embryogenesis
(2:2 segregation)

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44
Q

What is the outcome of a 3:1 segregation

A

gametes with 24 and 22 chromosomes are formed
conceptuses have either 47 or 45 chroms

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45
Q

Describe tertiary trisomy/monosomy segregation

A

3:1 segregation
trisomy: two normal chromosomes and one translocated chromosome move together (the centric portion contains the whole short arm of the derivative chromosome); most abnormal offspring have a tertiary trisomy; ex: der(22)t(11;22)(q23;q11)

monosomy: rare, if one der is very small and the amt of material missing is “monosomically small” there may be a viable conceptus (such as missing a subterminal portion)

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46
Q

Describe interchange trisomy/monosomy segregation

A

3:1 segregation
full autosome trisomy or full monosomy
trisomy: two translocated chroms and one normal chrom move together; more severe outcomes, less frequent only chromosomes 13, 18, 21, and 22 are viable trisomies
monosomy: only observed in PGD, likely very early arrested development of the embryo

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47
Q

Describe the result of 4:0 segregation

A

results in a double trisomy or a double monosomy
total nondisjunction of quadrivalent complex
is never viable

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48
Q

What are the ways to predict segregant outcomes

A
  1. assume alternate segregation is frequent and associated with phenotypic normality
  2. the least imbalanced, least monosomic gametes are most likely to produce a viable conceptus
  3. if the translocated segments are small in genetic content, adjacent 1 segregation is most likely to give rise to a viable, abnormal offspring
  4. if the centric segments are small in genetic content, adj 2 segregation is most likely to produce a viable, abnormal outcome
  5. if ONE chromosome in the quadrivalent is small in content, 3:1 segregation is most likely (the small chromosome could be a derivative OR chroms 13, 18, or 21)
  6. if the quadrivalent has properties of rules 3 and 5 OR 4 and 5, both adjacent and 3:1 segregations could give rise to a viable conceptus
  7. If the translocated and centric segments are large in content, NO viable offspring are possible
  8. If the translocated segments are BOTH subtelormeric, pairs may just join as bivalents (no quadrivalent) and segregate independently
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49
Q

What are the outcomes of different chromosomal imbalances

A

large: nonviable
moderate: a miscarriage or later fetal death
lesser: abnormal live birth (single segment imbalances from adjacent 1 segregation are usually the only viable conceptus

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50
Q

Describe the implications of translocation carriers on fetal outcome

A

61% of nonviable fetuses came from a translocation carrier mother and only 39% came from a carrier father
background pop risk for spontaneous abortion is 15%; the risk for a balanced t carrier ranges btwn 20-30% - risk depends on the size of the chromosome segment
couples with three or more miscarriages should undergo karyotype (some male carriers may be infertile due to arrested spermatogenesis)

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51
Q

What are some factors about translocation carriers that need to be determined before counseling a pt

A

mode of ascertainment
predicted type of segregation leading to potential viable gametes
sex of transmitting parent (mom more likely to pass on vs dad)
assessed imbalance of the potentially viable gamete

risk is ~25% for carriers to have an unbalanced fetal karyotype at amnio when there was a previously abnormal child
if the same balanced t is seen in a parent, there is NO INCREASED RISK for abnormality
in rare familial t’s, the rearrangement may promote mitotic malsegregation and disrupt a tumor suppressor gene, leading to increased cancer risks

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52
Q

What is the position effect

A

change in the level of gene expression caused by a change in a position of the gene relative to where it is normally found

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53
Q

What are the translocations implicated in cancer

A

chromosome 3 t’s, 5q, 11q, and 17p

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54
Q

What is a Robertsonian translocation

A

involves the acrocentric D and G group chromosomes. the t chromosome has 2 fused long arms and no short arms

heterologous t’s can pass through generations whereas homologous t’s are usually de novo (rare)
written as: 45,XX,der(14;21)(q10;q10)

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55
Q

What Robertsonian t’s are most commonly the cause of translocation DS

A

Rob(13q;21q) / Rob(14q;21q)

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56
Q

What are the three proposed mechanisms for Heterologous t’s

A
  1. centric fusion: fusion at the centromere forming a monocentric chromosome
  2. union following breakage in one short arm and one long arm: essentially a whole arm reciprocal t, resulting in a monocentric chromosome
  3. unition following breakage in both short arms: results in a DICENTRIC chromosome
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57
Q

What are the two mechanisms for Homologous t’s

A

fusion in the zygote of mat and pat homologs
can also result from an isochrom during meiosis

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58
Q

What is an isochromosome

A

nullisomic egg is “rescued” by reduplication of paternal homolog, leading to paternal UPD

59
Q

What explains the predominance of the rob(13q;14q) and rob(14q;21q)

A

possibly due to specific homologous, but inverted, segments in these chromosomes (homology encourages crossing over)

60
Q

What are the types of gametes that can be produced if someone has a rob translocation? what type of segregation does it follow?

A

2:1 segregation
alternate segregation will produce normal and balanced gametes
adjacent segregation produces two types of disomic gametes and nullisomic gametes

61
Q

In what instances is alternate segregation favored in males vs females and vice versa

A

males: translocation malsegregants are seen more often in men with oligospermia; in male carriers, t DS and t T13 are rare
females: have a ~20% risk for abnormal offspring; children of female carriers of rob’s have a ratio close to 60:40 for the balanced rob compared to the normal karyotype

62
Q

How can translocation trisomies be corrected

A

can be corrected due to mitotic loss of one normal homolog: results in UPD
UPD does NOT affect phenotype outcomes for chroms 13, 21, and 22
UPD DOES have imprinting effects for chroms 14 and 15; RARE; at prenatal dx, all balanced chromosome 14 and 15 Robertsonians need UPD analysis

63
Q

How can a monosomic conceptus be corrected to a disomic conceptus

A

typically results from a nullisomic ovum
rescue occurs by replication of the paternal homolog, resulting in uniparental paternal isodisomy (RARE)

64
Q

How can homologous Robertsonian t’s occur

A

due to the fusion of two paternal homologs (biparental inheritance)
due to a rearrangement of an isochrome where each long arm is the exact copy of the other, resulting in UPD
Only disomic and nullisomic gametes are possible
NO VIABLE GAMETES ARE POSSIBLE

65
Q

What is the risk of a rob(13q;14q) carrier to have an unbalanced offspring

A

0.7%

66
Q

What is rob(14q;21q) associated with and what are the offspring implications

A

associated with translocation DS resulting from adjacent segregation
in female heterozygotes, the risk of an affected fetus with translocation DS is ~15% at amino
the risk for a liveborn is ~10%
In male heterozygotes, the risk of an affected fetus with translocated DS is 1% at amnio

67
Q

What is the risk of a rob(13q;15q) carrier to have an unbalanced offspring

A

rare
risk is ~1% for t T13

68
Q

What is the risk of a rob(13q;21q) carrier to have an unbalanced offspring

A

female risk is ~15% to pass to a fetus at amnio
male risk to pass on rob is less than 1% at amnio and liveborn

69
Q

What is the risk of a rob(13q;22q) and rob(15q;21q) carrier to have an unbalanced offspring

A

risk is less than 1% for both males and females

70
Q

What is the risk of a rob(21q;22q) carrier to have an unbalanced offspring

A

risk for a liveborn is 10% in females and 1% in males

71
Q

Which Robertsonian translocations are lethal in utero

A

rob(14q;15q); rob(14q;22q); rob(15q;22q)

72
Q

Describe the process of X chromosome inactivation

A

around the blastocyst stage, lyonization occurs (~2wks post fertilization). One X chromosome in every cell of a female conceptus is randomly genetically inactivated
“dosage compensation” allows for the functional monosomy for most of the X chromosome (all progeny cells will have the same X inactivated, making the female a true mosaic

73
Q

What is the X inactivation center (XIC)? Where is it located?

A

Where X inactivation occurs, Xq13 and spreads in both directions along the chromosome
within the XIC is the XIST, a cis-acting gene that is only transcribed on the INACTIVE X chrom; functions by coating the entire chrom to prevent transcription, possibly by methylation/acetylation of DNA and chromatin folding

not all genes are inactivated- some loci are disomic; inactivation is blocked at Xp22.3, aka the pseudoautosomal region (PAR1), which pairs with Yp during meiosis; PAR2 in Xq and several other genes also remain active

74
Q

If a woman were to have a balanced X-autosome translocation, what would be the expected X-inactivation pattern?

A

The der(x) has the XIC and is inactive
The der (autosome) is active (for balance, both parts of the X chromosome involved in the translocation must be active; the “normal” X chromosome will be NONRANDOMLY inactivated in most cells)

you would rather have a balanced autosome rather than a monosomic autosome

75
Q

If a woman were to have an unbalanced X-autosome translocation, what would be the expected X-inactivation pattern?

A

INACTIVATION FAVORS THE LAST UNBALANCED CONCEPTUS. It results from non-random activation of the abnormal X
This can only occur if the abnormal X has an XIC; if the der(X) has a large autosomal translocated segment, then the normal X will be nonrandomly inactivated (to prevent monosomy of an autosome)
If the der(X) has no XIC, the X chromosome CANNOT be inactivated –> results in a partial X disomy

76
Q

Give an example of an X-autosome t that can cause Mendelian dz in females

A

t’s can disrupt genes associated with specific Mendelian conditions
when the normal X is inactivated due to a large autosome t, there is NO FUNCTIONAL COPY of the normal allele
ex: females with an Xp21-autosome t with DMD/BMD

77
Q

What occurs in males that have balanced X-autosome translocations

A

without intervention are infertile due to spermatogenic arrest

78
Q

What parts of the Y chrom make males phenotypically male

A

SRY, the testis determining gene is on Yp in PAR1
genes on Yq needed for reproduction are AZFa, b, and c
~1/2 of Yq has the genetic inactive heterochromatic region
Y chrom translocation (other than to an acrocentric chrom) could also cause sterility (but otherwise, normal male)

79
Q

What are the outcomes of a Yq and acrocentric p translocation

A

no gain or loss of euchromatin and phenotype is normal
~50% involve chromosome 15 (bc close homology between 15p and Yq heterochromatin, favoring the t)

80
Q

What can occur if Y material is translocated to an autosome, resulting in a 45 chromosome karyotype

A

SRY on Yp could be translocated to an autosome
associated with azoospermia and a Turner-like phenotype
ex: dic(Y;22)(q11.23;p11.2), dic(Y;15)(q11.2;p11.1)

81
Q

What can result from an X-Y translocation

A

Distal Xp is deleted with the loss of PAR1 (Xp genes= ARSE, SHOX, STS, KAL, MRX)
In males, loss of these regions can be detrimental
The X chromosome with the most genetic imbalance is usually inactivated. Since the most genetically stable is active, inactivation IS NO LONGER A RANDOM EVENT

82
Q

Describe the following: 46,X, der(X)t(X:Y)

A

partial monosomy Xp
Typically fertile with normal development

83
Q

Describe the following: 46,Y, der(X)t(X:Y)

A

nullisomic for Xp
usually the son of a t(X:Y) mother
if the breakpoint is DISTAL intelligence will be normal
if the breakpoint is PROXIMAL (containing a lot of genes) there will be mental delay

most males are infertile, the majority of these cases are familial

84
Q

What can result from an X-X t? How does this occur

A

46,X,der(X)t(Xp;Xq) results in a del dyp of Xp/Xq or vice versa
results from unequal crossing over between the two X chromosomes in the oocyte
could also occur when an X chromosome folds onto itself (origin is probably paternal in this case)
will present with pubertal and menstrual abnormalities, as well as infertility

85
Q

How would you counsel someone that has an X autosome translocation

A

~50% of female and almost all male carriers are infertile
fertile females are at risk of having abnormal offspring
ranges from mild (XO/XXY) to severe (partial X disomy or autosomal aneuploidy)
each t needs to be assessed individually, dependent on which pieces are involved

86
Q

What would the outcome be for single segment translocation with a large X segment

A

partial turner, partial KS, and partial XXX syndromes

a single segment translocation with a small X segment could have the above AND a functional disomy for distal Xp or Xq

87
Q

What would the outcome be for single segment translocation with a large autosomal segment

A

has a risk for partial autosomal monosomy or trisomy

any 2-2 unbalanced segregants (likely adj-1for the least amt of imbalance) from a double segment translocation has a combined deldup risk (since there is not much material or too much, SAB is likely)

88
Q

What can you tell expectant parents if a balanced X-autosome is detected prenatally

A

a female fetus with the same t may not have the same phenotype as mom (X inactivation may be different, resulting in partial X disomy)
male carriers range from normal phenotype to offspring with major genital defects (u/s recommended to look for the presence of typical male genitalia)

89
Q

What can you tell expectant parents if a Y-autosome translocation is detected prenatally

A

in the apparently balanced: male risk for infertility must be assessed based on t breakpoints (can do ICSI, IVF, and PGD)

for those with Yq and actocentrics: no clinical significance (very minor risk of T15 with corrected to UPD if t(Yq;15p))

Cryptic 45,X,t(Yp-acrocentric): stable and phenotypically normal

90
Q

What can you tell expectant parents if a Y-X translocation is detected prenatally

A

Female offspring are typically fertile and of typical intelligence (50% chance of having offspring with the translocation)
male offspring may be abnormal depending on the loci involved (almost always infertile, offer ART)

91
Q

What can you tell expectant parents if an X-X translocation is detected prenatally

A

associated with infertility
in small imbalances when fertility is possible, daughters will have same phenotype as mom
male pregnancy would most likely miscarry due to X nullisomy/disomy (if del/dup is small, it may be viable, but with major phenotypic abnormalities)
offspring with the normal X would be unaffected

92
Q

What is an inversion

A

an intrachromosomal structural rearrangement in which a chromosome is reversed end to end; a single chromosome undergoes breakage and rearrangement within itself

93
Q

What is a pericentric inversion

A

involves the centromere; break in the short AND long arm (more phenotypic consequences)

94
Q

What is a paracentric inversion

A

no centromere involved; breaks in either the short OR long arm

95
Q

What are the results of autosomal pericentric inversions

A

heterozygotes may produce unbalanced gametes due to recombination within inverted segments during meiosis

inversion homolog and normal homolog do not match perfectly; therefore, and inv loop is formed to align the segments of both homologs. results in:
1. normal homolog (aa’)
2. inverted homolog (bb’)
3. a recombinant homolog (cc’dup(p)- a dup of part of the short arm and del of part of the long arm)
4. a recombinant homolog (dd’(dup(q)- a dup of part of the long arm, del of part of the short arm)

96
Q

What are the karyotypes of a son for this father’s karyotype: 46,XY, inv(7)(p.14q36.3)

A

heterozygotes with distally large inverted segments CANNOT have viable abnormal offspring

46,XY,rec(7)dup(7q)inv(7)(p.14q36.3)
partial trisomy 7q, monosomy 7p

46,XY,rec(7)dup(7p)inv(7)(p.14q36.3)
partial trisomy 7p, monosomy 7q

mosaicism for a balanced inv rarely occurs

97
Q

What results from an X pericentric inversion

A

forms the same way as autosome inv
breakpoints in the X critical region may influence the phenotype in females
imbalances in the 46,X,rec(X) females may be “corrected” by selective inactivation of the abnormal X
46,Y,rec(X) will have partial X nullisomy and functional X disomy

can be transmitted by both males and females

98
Q

What can occur in a female with a heterozygous inv(X)

A

appear normal
breaks in the X critical region (q13-q22/q22-q26) can cause gonadal dysfunction (primary amenorrhea, premature menopause)
ovum with a recombinant X has different outcomes depending on the X or Y bearing sperm

x bearing sperm: del(Xq)/dup(Xp): normal or tall stature, ovarian dysgenesis; del(Xp)/dup(Xq): short stature, normal ovarian function
y bearing sperm: nullisomy for the deleted X segment. results in major congenital anomalies and neurodevelopmental compromise; disomy also results in major deleterious effects

99
Q

What are the reproductive outcomes of a hemizygote inv(X) carrier

A

no effect on phenotype or reproduction because there is no recombination in the inv segment during meiosis
all daughters are heterozygous; sons receive mom’s normal X

100
Q

What are the phenotypic effects of having inv(Y)(p.11.2q13)

A

common, considered a normal variant and has no phenotypic or reproductive effects

101
Q

Who do you offer prenatal testing to when considering inversions

A

heterozygotes whose family had a recombinant child
heterozygotes for an inversion
heterozygotes with inversions involving chrms 13, 18, and 21
molecular analysis for the invs involving chroms 15q11-q13 to r/o PWS and AS

102
Q

What are the gamete results of someone with a paracentric inversion

A

normal, inverted, acentric, and dicentric chroms (acentric and dicentric gametes are nonviable)
therefore, heterozygotes cannot produce unbalanced offspring (will produce normal or balanced zygotes)

genetic risk factor for abnormal offspring is VERY SMALL

103
Q

What are three ways DSDs can occur

A

In utero exposure to sex hormones
Random developmental variation (mom/dad with ambiguous genitalia)
Chromosomal and genetic anomalies

104
Q

What is dosage compensation and how does it relate to X chromosome aneuploidies

A

x chromosome aneuploidies are typically associated with “little” phenotypic abnormality due to dosage compensation
however, some loci on additional X chromosomes are still active, leading to mild phenotypic abnormalities
in females with abnormal X’s, X-inactivation is usually non-random (if the abnormality is a microdel/dup, the inactivation pattern may be RANDOM)

105
Q

How does a ring chromosome form

A

deletion of Xp and Xq (or dup of both)
if the XIST is missing, an abnormal phenotype will occur (FUNCTIONAL X DISOMY)

106
Q

What is an isochromosome

A

loss of one arm of the chromosome and replacement of it with an exact copy of the other arm

107
Q

How frequent are chromosomal abnormalities in all conceptions

A

7.5%

108
Q

How frequent are chromosome abnormalities in first trimester SAB

A

50%

109
Q

How frequent are chromosome abnormalities in multiple miscarriages

A

2-5%

110
Q

What two mosaic trisomies (other than 13, 18, and 21) are viable

A

mosaic trisomy 8 and 9

111
Q

What percentage of trisomies are due to maternal nondisjunction’s

A

95%

112
Q

What percentage of trisomies are due to errors in meiosis I

A

80%

113
Q

What percentage of trisomies are conceptuses that spontaneously abort

A

78%

114
Q

What percentage of DS is caused by 47,XX,+21

A

95%

115
Q

What percentage of DS is caused by an unbalanced Robertsonian translocation

A

4-5% from a parent with a 45,XX,der(14;21)(q10;q10)

116
Q

What percentage of DS is caused by mosaic 47,XX,+21

A

~1%

117
Q

Define SAB as written by ACOG

A

nonviable, intrauterine pregnancy with an empty gestational sac OR a gestational sac with an embryo or fetus with no heart activity in the first 6-7wks of gestation

118
Q

How often do SAB occur in all clinically recognized pregnancies

A

10% or 1 in 10

119
Q

How often does SAB account for pregnancy losses in the first trimester

A

~80%

120
Q

What is triploidy caused by? What occurs if it is maternal in origin or paternal in origin

A

caused by polyspermy/dispermy
usually spontaneously abort
when extra chromosome complement is maternal (digynic): fetus with IUGR, very small placenta
when extra chromosome complement is paternal (diandric): well grown fetus, large cystic placenta

121
Q

What is uniparental disomy? What are the GENERAL features of conditions that could result

A

inheritance of both homologs from the same parent
most UPD pts have: Intrauterine and post natal growth delay, mental disabilities, congenital malformations, and dysmorphic features
could also result in homozygosity for an AR gene

122
Q

What type of testing can confirm dx of a uniparental disomy? What cannot?

A

KARYOTYPES ARE NORMAL
can only be demonstrated at the molecular level

123
Q

What is isodisomy

A

both homologs are identical
polymorphic DNA markers show both homologs with the same haplotype (group of alleles inherited from a single parent) from one parent
results from nondisjunction in MeII or a mitotic error

124
Q

What is heterodisomy

A

homologs are different
polymorphic DNA markers show the two chromosomes have the same haplotypes as the chromosome pair from one parent
results from nondisjunction in MeI

125
Q

How does segmental UPD occur? What is it?

A

only part of the chromosome comes from the same parent –> is the result of crossing over

126
Q

How do epigenetics play into UPD and gene expression in general

A

same genotype will produce a different phenotype depending on the sex of the transmitting parent (ex: methylation as an imprinting mechanism)
imprinted DNA segments function monoallelically (either maternal or paternal segment will be active; if both segments originate from one parent there will be DOUBLE the amount of expression OR no expression, leading to the phenotypic defects in UPD
IF THE CHROMOSOME IS NOT SUBJECT TO IMPRINTING, UPD HAS NO EFFECT

127
Q

What does complete paternal UPD cause

A

for all 46 chromosomes, forms a complete hydatidiform mole
one maternal and two paternal chromosome complements produces a triploid fetus

128
Q

What does complete maternal UPD cause

A

for all 46 chromosomes, forms a benign cystic ovarian teratoma
one maternal and two paternal chromosome complements produces a triploid fetus

129
Q

What are the ways in which UPD can occur

A

gamete complementation
trisomic rescue
monosomic rescue
mitotic error

two abnormal events must occur simultaneously OR sequentially in the above:
1. errors can be both meiotic
2. meiotic followed by mitotic
3. both mitotic
4. the original abnormality is sporadic (no recurrence risk)

ONLY RISK is AMA, meiotic nondisjunction leading to UPD

130
Q

What is gamete complementation in reference to UPD

A

one parent produces a nullisomic gamete and the other produces a disomic gamete

131
Q

What is trisomic rescue in reference to UPD

A

CAUSES THE MOST UPD
trisomic early conceptus will lose one of the extra chromosomes
restores the disomy
if the “wrong” chromosome is lost, the zygote will have either mat or pat UPD

132
Q

What is monosomic rescue in reference to UPD

A

if a nullisomic gamete is produced at meiosis, the conceptus will be monosomic
mitotic correction replicates the normal homolog producing UPD isodisomy

133
Q

What is a mitotic error that can lead to UPD

A

occurs in a typical conception leading to trisomy or monosomy
in trisomy: the “wrong” chromosome is lost producing either mat or pat UPD
in monosomy: the chromosome is duplicated

134
Q

How does segmental UPD occur?

A

can arise by post-zygotic somatic recombination (UPD segment is distal; rest of chromosome will have typical biparental inheritance)
can also arise by meiotic nondisjunction producing a disomic gamete causing a trisomic conception to occur leading to mitotic crossing over between a mat and pat chromatid resulting in one of the chromosomes being loss (trisomy rescue)
will have an effect if the chromosome has loci subject to imprinting

135
Q

UPD has been described for all chromosomes except…

A

12, 18, and 19

136
Q

Describe the cytogenetics of PWS

A

caused by the absence of activity of the genes in 15q11-13 under control of SNRPN
deletions cause ~70% (removes about 4Mb in 15q11-13, encompasses the PWS and AS structural genes and the IC)
can also result from passing an unbalanced t OR inversion of chrom 15 (ALWAYS do UPD analysis at prenatal testing)
~25% is due to UPD
PWS: both chromosome 15’s are MATERNAL (80% results from maternal nondisjuction in MeI, AMA associated)
~1% result from IC defects (pts have biparental inheritance with a uniparental methylation pattern and gene expression; can also be microdeletion)
uncommonly, PWS results from a cytogenetically detectable rearrangement

137
Q

Describe the cytogenetics of Angelman syndrome

A

AS caused by absence of activity of the UBE3A gene
deletions cause ~70% (removes about 4Mb in 15q11-13, encompasses the PWS and AS structural genes and the IC)
can also result from passing an unbalanced t OR inversion of chrom 15 (ALWAYS do UPD analysis at prenatal testing)
3-5% of AS reusults from UPD
AS: both chromosomes are PATERNAL
usually results from monosomy 15 correction of a nullisomic ovum, AMA associated
2-4% due to IC defects (pts have biparental inheritance with a uniparental methylation pattern and gene expression; can also be microdeletion)
AS can also result from a mutation in UBE3A (also seen in pts with no known etiology, suspected epigenetic error)

138
Q

What are the five types of Angelman syndrome

A

Type 1: Classical del of 15q11-13
Type 2: paternal UPD 15
Type 3a: IC microdeletion
Type 3b: Functional defect of IC
Type 4: UBE3A mutation
Type 5: no known etiology, possible epigenetic error

139
Q

What is the most common chromosome translocation

A

13;14

140
Q

What is the Philadelphia chrom? What is it associated with?

A

9;22 t
associated with SML (small lymphocytic lymphoma/Chronic myeloid leukemia) and AML (acute myeloid leukemia) cancers

141
Q

Describe what this means structurally: 46,XX, der(15), t(15;22)(q26.2;q12)

A

derivative chrom 15 has the centromere of chrom 15
end of chrom 15 has been replaced with the end of chrom 22
extra material of 22, missing material of 15

142
Q

What causes symptoms from a ring chromosome? What are the features? What is the etiology

A

occurs when there is a del at both ends of the chromosome and the ends fuse
symptoms due to deleted genes at terminal end
features depend on the chromosome bust most include growth delay
can be inherited but most are de novo

143
Q

What is a marker chrom? How is it identified? What is the etiology?

A

extra small chrom; no distinct banding pattern so need a CMA to determine what genetic info it includes/what chrom it is from
can cause symptoms if it contains a region that would lead to a dup syndrome
can be inherited or de novo; 1/3 are familial

Board Review 2024 (29 decks)

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