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M2M2 > Structural Chromosomal Abnormalities > Flashcards

Structural Chromosomal Abnormalities Flashcards

1
Q

Visualizing structural abnormalities -

A

cytogenetics if >5mb

FISH or chromosomal microarray if smaller

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2
Q

What kind of DNA damage is required for rearrangements?

A

Double strand breaks

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3
Q

Balance chromosomal aberrations

A

Normal complement of chromosomal material

e.g. reciprocal translocations
Robertsonian translocations
Inversions

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4
Q

Are Robertsonian translcations balanced?

A

Yes

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5
Q

Unbalanced chromosomal aberrations
Results in?
Examples?

A 
Results in abnormal chromosomal content
Deletions
duplications
isochromosomes
Marker (Ring) chromosomes
recombinant chromosomes
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6
Q

Why are rearrangement common during meiosis?

A

because DSBs are required

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7
Q

Where do most breakpoints occur?

A

Regions in which repeated sequences are prevalent

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8
Q

Individuals with these rearrangements have normal complements of chromosomal material, meaning there is no loss of genetic material

A

Balanced

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9
Q

Even though there’s no loss of genetic material, what is a consequence of balanced chromosomal rearrangements?

A

They have varying stability during meiosis and mitosis

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10
Q

Inversions

A

occur when one chromosome undergoes two double stranded breaks of the DNA backbone and the intervening sequence is inverted prior to the rejoining of the broken ends

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11
Q

Pericentric inversions

A

include the centromere

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12
Q

paracentric inversions

A

exclude the centromere

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13
Q

Chromosomes with inversions can have normal genetic complement, and therefore carriers may have no phenotype. However, during meiosis, a loop to maximize the association between homologs is created. If a crossover occurs within the inverted region of a paracentric inversion what happens?

A

If a crossover occurs within the inverted region, both dicentric (2 centromeres) chromosomes and acentric (no centromere) chromosomes can be generated, leading to chromosome breakage or loss

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14
Q

Reciprocal translocations - balanced or unbalanced?

A

balanced

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15
Q

reciprocal translocations results from?

A

breakage and rejoining of non homologous chromosomes, with a reciprocal exchange of broken segments.

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16
Q

Reciprocal translocations carriers have increased risk of?

A

unbalanced gametes

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17
Q

Because carriers of reciprocal translocations are frequently phenotypically normal, how are they usually uncovered?

A

when couples have spontaneous abortions

males are infertile

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18
Q

What happens when chromosomes of a carrier of a balanced reciprocal translocation pair at meiosis?

A

a quadrivalent is formed

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19
Q

Reciprocal translocation - meiotic quadrivalent

Which segregation pattern will result in normal chromosome complement in gametes?

A

Alternate segregation

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20
Q

Alternate segregation of quadrivalents from reciprocal translocations results in gametes that have….?

A

Either the normal chromosome complement
or
two reciprocal translocation chromosomes, both of which are balanced with respect to chromosome complement

*See slide 8

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21
Q

What happens if adjacent segregation occurs with the quadrivalent in meiosis?

A

adjacent segregation leads to unbalanced gametes

See slide 8

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22
Q

When can a balanced (Apparently) translocation manifest phenotypically in the carrier?

A

if the breakpoint occurs in a gene, disrupting its function

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23
Q

Reciprocal Translocations: Quadrivalent Formation at Meiosis I… how do the homologues arrange themselves?

A

At zygotene, the partner homologues, both normal and translocated arrange themselves to maximize sequence pairing

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24
Q

Reciprocal translocation - quadrivalent segregation is described by?

A

The relationship of the centromeres to one another

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25
Q

In ___________ segregation, centromeres of homologues go to opposite poles

A

alternate

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26
Q

Alternate segregation leads to?

A

gametes with normal choromosomes

gametes with both derivatives (balanced)

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27
Q

In __________ segregation, next door centromeres go to the same pole

A

adjacent

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28
Q

adjacent segregation –>

A

abnormal segregation

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29
Q

Adjacent segregation is the most common form of malsegregation when…?

A

the translocated segments are relatively small

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30
Q

Adjacent segregation results in?

A

Trisomy and monosomy for translocated segments

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31
Q

What helps to determine the potential viability of zygote(s)

A

The size of the translocated segment - larger translocated segments offer more opportunity for recombinations

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32
Q

Balanced translocation carriers… risk to have unbalanced progeny?

A

Ranges from 0-30% depending on the type of translocation

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33
Q

Balanced translocation carriers

–> The risk for unbalanced progeny depends on

A

size of exchanged material

sex of carrier: maternal more likely to have unbalanced offspring

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34
Q

What are Robertsonian Translocations?

A

Structural chromosomal rearrangement

centric fusion

joining of two acrocentric chromosomes at the centromere, short arm

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35
Q

Robertsonian Translocations occur when there is fusion of two acrocentric chromosomes with their centromeric regions, do we lose any DNA?

A

We lose the short arm DNA containing satellite DNA and rDNA repeats - but not any significant DNA

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36
Q

Roberstonian Translocations - are they considered balanced?

A

Yes, while Robertsonian Translocations result in reduction in chromosome number, they are considered balanced rearrangements because the loss of some rDNA repeats is not deleterious

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37
Q

Carriers of Robertsonian Translocations and offspring risks?

A

Carriers of Robertsonian Translocations are phentoypically normal, but these rearrangements may lead to unbalanced karyotypes for their offspring, resulting in monosomies and trisomies

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38
Q

Human Acrocentric chromosomes

A

13, 14, 15, 21, and 22

39
Q

Is there a risk of loss of euchromatin with Robertsonian translocations?

A

No, there is no euchromatin on the p arm of acrocentric chromosomes

40
Q

What is the most common type of chromosomal rearrangement?

A

Robertsonian translocations

41
Q

Is there a risk to offspring if parent has Robertsonian translocations?

A

Yes, risk of having unbalanced karyotype

42
Q

Robertsonian translocations and fertility

A

Increased prevalence of RT in infertile men

43
Q

Most common Robertsonian Translocation, and two other common RT

A

13;14 = 75% of all RTs (mos common translocation in humans)

14;21
21;21

44
Q

Are Robertsonian Translocations de novo or familial?

A

They can be de novo or familial

45
Q

De Novo unbalanced Robertsonian Translocations

If we have 46 chromosomes with normal homologue plus RT “homologue” it leads to __________

A

Trisomy

46
Q

RT invovling chromosomes 13 and 21 can lead to viable trisomies: tri 13 and 21

What would the nomenclature of unbalanced RT 14;21 with normal 21 plus RT look like in a female?

A

46,XX,+21,der(14;21)(q10;q10)

47
Q

What would be the nomenclature for trisomy 13 derived from RT (13;14) in a male?

A

46,XY,+13,der(13;14)(q10;q10)

48
Q

What would the nomenclature be for a balanced translocation of 21 to 14 in male?

A

45,XY,der(14;21)(q10;q10)

49
Q

What would be the nomenclature for an unbalanced translocation of 21 to 14 in male

resulting in trisomy 21?

A

46,XY,der(14;21)(q10;q10),+21

50
Q

Are familial or de novo inversions more common?

A

familial

51
Q

Incidence of inversions?

A

as high as 1% in population

52
Q

Inversion carriers phenotype?

A

Normally normal

53
Q

Pericentric inversion

A

Inverted segment includes the centromere

break in both p and q arms

54
Q

Pericentric inversion nomenclature of chromosome 9 involving break at p24 and q21? In female

A

46,XX,inv(9)(p24q12)

55
Q

Common benign pericentric inversions in the population are called?

A

Heteromorphic variants

56
Q

What are common heteromorphic variant pericentric inversions containing constitugive heterochromatin in the population?

A 
9qh
16qh
1qh
Yqh
pericentric region of 2 or e
57
Q

Benign pericentric inversion in the population containing G positive bands?

A

19p12

58
Q

Are benign pericentric inversions familial or de novo?

A

Almost always familial

59
Q

Are benign pericentric inversions associated wtih increased spontaneous abortions / infertility / or recombinant offspring?

A

No!

60
Q

Which pericentric inversion is so common in the populace (2-3%) that it is no longer even reported?

A

9qh

report as 46,XX

61
Q

Pericentric inversion behavior during meiosis?

A

Pericentric inversions form a loop structure during homologue pairing of meiosis

Issue: how to get maximal pairing of like sequences between two homologues

Potential for forming recombinant chromosomes

62
Q

What is the homologue pairing stage of meiosis called?

A

Zygotene

63
Q

Outcomes of recombination in pericentric inversion carriers?

A

One recombination even is predicted within the inverted segment of the inversion chromosome and the homologous sequence in the normal chromosome

Crossover between two non-sister chromatids–> Gives rise to:
Two complementary recombinants

Duplication of long arm, deletion of short arm flanking segment

Deletion of long arm, duplication of short arm flanking segment

64
Q

Meiotic Recombination in inversion carriers

Possible gametes? (2)

A

Normal, unrearranged
Inversion, balanced carrier
- combined about 50%

Two complementary recombinants
- usually one compatible with liveborn and one lethal, but not always

see slide 32

65
Q

Recombinant 8 “rec 8”

Derived from?

A

inversion 8 carrier

46,XX inv(8)(p23.1q22.1)

66
Q

Recombinant 8 results in two negative outcomes…

A

Trisomy for 8q22.1

Monosomy for 8p23.1

67
Q

Rec (8) phenotype

A

Developmental delay
Congenital heart disease
Hypertelorism (large distance between eyes)
Thin upper lip

68
Q

Inversion 8 carriers at risk for?

A

rec(8) offspring

69
Q

Inversion 8 carrier

recurrence risk

A

6.7%

70
Q

Inversion 8 carrier

risk for miscarriage?

A

not significantly increased

71
Q

Recombinant 8 syndrome

illustrates what effect

A

founder effect

first described in Hispanic families in West

Kindreds with ancestral lines originating in teh San Luis Valley

Postualte a single common ancestory (founder) with inv(8) 2-300 years ago

72
Q

Paracentric inversion

A

Inversion segment excludes centromere

two breaks within the same chromosome arm

73
Q

Paracentric inversion dectection?

A

May be more difficult to detect

Under ascertained

74
Q

Are paracentric inversions familial or de novo

A

Familal or sporadic

75
Q

Paracentric inversions and reported disease (2)

A

inv(11)(p13p15) aniridia (absence of iris)

Xp/q inversion and Turner syndrome anomalies

76
Q

Paracentric inversions…

Abnormal meiotic products?

A

Either dicentric or acentric

77
Q

Paracentric inversions
Inversion loop and recombination products…
Where is the centromere with regard to the inversion loop?

A

Outside the loop

Resulting in dicentric and acentric fragments

78
Q

Segmental duplications can cause aberreant recombination events that give rise to either duplications or deletions… Genomic duplication followed by adaptive mutation is considered one of the primary forces for what?

A

Evolution of new gene function

79
Q

Contiguous gene syndromes/microdeletions and microduplications are defined as?

A

abnormal phenotypes caused by gain or loss of a set of neighboring genes

80
Q

What is del(22)q11.2

A

Cat eye syndrome

Example of contiguous gene Del/DUP syndrome

81
Q

What are chromosome 22 rearrangements mediated by?

A

Segmental duplication

82
Q

Cat eye syndrome is an example of

A

Chromosome 22 rearrangement mediated by gene duplication

83
Q

Deletion or Duplication 22q11.2 syndrome

Caused by?
Effected protein and fx?

A

Caused by disturbance of migration of neural crest cells into the pharyngeal arches and pouches resulting in cleft lip/palate and heart defects

Thymus defects: T cell
Parathyroid defects: hypocalcemia

Critical protein: TBX-1 - transcription factor that is important for neural crest cell migration!

84
Q

Wolf-Hirschorn syndrome

A 
del(4p16.3)
Facial clefting
Prominent ears
microcephaly 
intellectual disabilities
85
Q

Cri du chat syndrome

A 
del(5p15.2)
microcephaly
characteristic cry
seizures
intellectual disability
86
Q

Williams syndrome

A

del(7q11.2)
Congenital heart disease
short stature

87
Q

Langer Giedion syndrome

A

del(8q24.1)
Tricho-rhino pharangeal syndrome - characterized by thin, sparse scalp hair, unusual facial features, and multiple abnormalities affecting the “growing ends” (epiphyses) of certain bones, especially those in the hands and feet.
Multiple exostoses - (benign outgrowth of cartilagenous tissue)

88
Q

WAGR syndrome

A 
del(11p13)
Wilms tumor
aniridia 
genitourinary anomalies
intellectual disability
89
Q

Beckwith-Wiedemann syndrome

A 
dup(11p15.5) paternal
overgrowth
omphalocele (gi outside)
Wilms tumor
other tumors
90
Q

Angelman Syndrome

A

del(15q11-q13) maternal
seizures
intellectual disabilties

91
Q

Prader Willi syndrome

A 
del(15q11-q13) paternal 
hypotonia
hypopigmentation 
hypogenitalism 
obesity
92
Q

Miller-Dieker syndrome

A

del(17p13.3)
lissencephaly (no brain convolutions)
profound intellectual disability

93
Q

DiGeorge syndrome

A

del(22q11.2)
absent or hypoplastic thymus and parathyroids
congenital heart disease
Velo-Cardio-Facial Syndrome
- cleft palate, lateral nasal buildup, cardiac septal defects

M2M2 (27 decks)

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