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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
In ___________ segregation, centromeres of homologues go to opposite poles
alternate
26
Alternate segregation leads to?
gametes with normal choromosomes | gametes with both derivatives (balanced)
27
In __________ segregation, next door centromeres go to the same pole
adjacent
28
adjacent segregation -->
abnormal segregation
29
Adjacent segregation is the most common form of malsegregation when...?
the translocated segments are relatively small
30
Adjacent segregation results in?
Trisomy and monosomy for translocated segments
31
What helps to determine the potential viability of zygote(s)
The size of the translocated segment - larger translocated segments offer more opportunity for recombinations
32
Balanced translocation carriers... risk to have unbalanced progeny?
Ranges from 0-30% depending on the type of translocation
33
Balanced translocation carriers | --> The risk for unbalanced progeny depends on
size of exchanged material sex of carrier: maternal more likely to have unbalanced offspring
34
What are Robertsonian Translocations?
Structural chromosomal rearrangement centric fusion joining of two acrocentric chromosomes at the centromere, short arm
35
Robertsonian Translocations occur when there is fusion of two acrocentric chromosomes with their centromeric regions, do we lose any DNA?
We lose the short arm DNA containing satellite DNA and rDNA repeats - but not any significant DNA
36
Roberstonian Translocations - are they considered balanced?
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
37
Carriers of Robertsonian Translocations and offspring risks?
Carriers of Robertsonian Translocations are phentoypically normal, but these rearrangements may lead to unbalanced karyotypes for their offspring, resulting in monosomies and trisomies
38
Human Acrocentric chromosomes
13, 14, 15, 21, and 22
39
Is there a risk of loss of euchromatin with Robertsonian translocations?
No, there is no euchromatin on the p arm of acrocentric chromosomes
40
What is the most common type of chromosomal rearrangement?
Robertsonian translocations
41
Is there a risk to offspring if parent has Robertsonian translocations?
Yes, risk of having unbalanced karyotype
42
Robertsonian translocations and fertility
Increased prevalence of RT in infertile men
43
Most common Robertsonian Translocation, and two other common RT
13;14 = 75% of all RTs (mos common translocation in humans) 14;21 21;21
44
Are Robertsonian Translocations de novo or familial?
They can be de novo or familial
45
De Novo unbalanced Robertsonian Translocations If we have 46 chromosomes with normal homologue plus RT "homologue" it leads to __________
Trisomy
46
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?
46,XX,+21,der(14;21)(q10;q10)
47
What would be the nomenclature for trisomy 13 derived from RT (13;14) in a male?
46,XY,+13,der(13;14)(q10;q10)
48
What would the nomenclature be for a balanced translocation of 21 to 14 in male?
45,XY,der(14;21)(q10;q10)
49
What would be the nomenclature for an unbalanced translocation of 21 to 14 in male resulting in trisomy 21?
46,XY,der(14;21)(q10;q10),+21
50
Are familial or de novo inversions more common?
familial
51
Incidence of inversions?
as high as 1% in population
52
Inversion carriers phenotype?
Normally normal
53
Pericentric inversion
Inverted segment includes the centromere | break in both p and q arms
54
Pericentric inversion nomenclature of chromosome 9 involving break at p24 and q21? In female
46,XX,inv(9)(p24q12)
55
Common benign pericentric inversions in the population are called?
Heteromorphic variants
56
What are common heteromorphic variant pericentric inversions containing constitugive heterochromatin in the population?
``` 9qh 16qh 1qh Yqh pericentric region of 2 or e ```
57
Benign pericentric inversion in the population containing G positive bands?
19p12
58
Are benign pericentric inversions familial or de novo?
Almost always familial
59
Are benign pericentric inversions associated wtih increased spontaneous abortions / infertility / or recombinant offspring?
No!
60
Which pericentric inversion is so common in the populace (2-3%) that it is no longer even reported?
9qh | report as 46,XX
61
Pericentric inversion behavior during meiosis?
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
What is the homologue pairing stage of meiosis called?
Zygotene
63
Outcomes of recombination in pericentric inversion carriers?
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
Meiotic Recombination in inversion carriers Possible gametes? (2)
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
Recombinant 8 "rec 8" | Derived from?
inversion 8 carrier | 46,XX inv(8)(p23.1q22.1)
66
Recombinant 8 results in two negative outcomes...
Trisomy for 8q22.1 | Monosomy for 8p23.1
67
Rec (8) phenotype
Developmental delay Congenital heart disease Hypertelorism (large distance between eyes) Thin upper lip
68
Inversion 8 carriers at risk for?
rec(8) offspring
69
Inversion 8 carrier | recurrence risk
6.7%
70
Inversion 8 carrier | risk for miscarriage?
not significantly increased
71
Recombinant 8 syndrome | illustrates what effect
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
Paracentric inversion
Inversion segment excludes centromere two breaks within the same chromosome arm
73
Paracentric inversion dectection?
May be more difficult to detect | Under ascertained
74
Are paracentric inversions familial or de novo
Familal or sporadic
75
Paracentric inversions and reported disease (2)
inv(11)(p13p15) aniridia (absence of iris) Xp/q inversion and Turner syndrome anomalies
76
Paracentric inversions... | Abnormal meiotic products?
Either dicentric or acentric
77
Paracentric inversions Inversion loop and recombination products... Where is the centromere with regard to the inversion loop?
Outside the loop Resulting in dicentric and acentric fragments
78
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?
Evolution of new gene function
79
Contiguous gene syndromes/microdeletions and microduplications are defined as?
abnormal phenotypes caused by gain or loss of a set of neighboring genes
80
What is del(22)q11.2
Cat eye syndrome | Example of contiguous gene Del/DUP syndrome
81
What are chromosome 22 rearrangements mediated by?
Segmental duplication
82
Cat eye syndrome is an example of
Chromosome 22 rearrangement mediated by gene duplication
83
Deletion or Duplication 22q11.2 syndrome Caused by? Effected protein and fx?
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
Wolf-Hirschorn syndrome
``` del(4p16.3) Facial clefting Prominent ears microcephaly intellectual disabilities ```
85
Cri du chat syndrome
``` del(5p15.2) microcephaly characteristic cry seizures intellectual disability ```
86
Williams syndrome
del(7q11.2) Congenital heart disease short stature
87
Langer Giedion syndrome
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
WAGR syndrome
``` del(11p13) Wilms tumor aniridia genitourinary anomalies intellectual disability ```
89
Beckwith-Wiedemann syndrome
``` dup(11p15.5) paternal overgrowth omphalocele (gi outside) Wilms tumor other tumors ```
90
Angelman Syndrome
del(15q11-q13) maternal seizures intellectual disabilties
91
Prader Willi syndrome
``` del(15q11-q13) paternal hypotonia hypopigmentation hypogenitalism obesity ```
92
Miller-Dieker syndrome
del(17p13.3) lissencephaly (no brain convolutions) profound intellectual disability
93
DiGeorge syndrome
del(22q11.2) absent or hypoplastic thymus and parathyroids congenital heart disease Velo-Cardio-Facial Syndrome - cleft palate, lateral nasal buildup, cardiac septal defects

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