Structural Chromosomal Abnormalities Flashcards
Visualizing structural abnormalities -
cytogenetics if >5mb
FISH or chromosomal microarray if smaller
What kind of DNA damage is required for rearrangements?
Double strand breaks
Balance chromosomal aberrations
Normal complement of chromosomal material
e.g. reciprocal translocations
Robertsonian translocations
Inversions
Are Robertsonian translcations balanced?
Yes
Unbalanced chromosomal aberrations
Results in?
Examples?
Results in abnormal chromosomal content Deletions duplications isochromosomes Marker (Ring) chromosomes recombinant chromosomes
Why are rearrangement common during meiosis?
because DSBs are required
Where do most breakpoints occur?
Regions in which repeated sequences are prevalent
Individuals with these rearrangements have normal complements of chromosomal material, meaning there is no loss of genetic material
Balanced
Even though there’s no loss of genetic material, what is a consequence of balanced chromosomal rearrangements?
They have varying stability during meiosis and mitosis
Inversions
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
Pericentric inversions
include the centromere
paracentric inversions
exclude the centromere
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?
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
Reciprocal translocations - balanced or unbalanced?
balanced
reciprocal translocations results from?
breakage and rejoining of non homologous chromosomes, with a reciprocal exchange of broken segments.
Reciprocal translocations carriers have increased risk of?
unbalanced gametes
Because carriers of reciprocal translocations are frequently phenotypically normal, how are they usually uncovered?
when couples have spontaneous abortions
males are infertile
What happens when chromosomes of a carrier of a balanced reciprocal translocation pair at meiosis?
a quadrivalent is formed
Reciprocal translocation - meiotic quadrivalent
Which segregation pattern will result in normal chromosome complement in gametes?
Alternate segregation
Alternate segregation of quadrivalents from reciprocal translocations results in gametes that have….?
Either the normal chromosome complement
or
two reciprocal translocation chromosomes, both of which are balanced with respect to chromosome complement
*See slide 8
What happens if adjacent segregation occurs with the quadrivalent in meiosis?
adjacent segregation leads to unbalanced gametes
See slide 8
When can a balanced (Apparently) translocation manifest phenotypically in the carrier?
if the breakpoint occurs in a gene, disrupting its function
Reciprocal Translocations: Quadrivalent Formation at Meiosis I… how do the homologues arrange themselves?
At zygotene, the partner homologues, both normal and translocated arrange themselves to maximize sequence pairing
Reciprocal translocation - quadrivalent segregation is described by?
The relationship of the centromeres to one another
In ___________ segregation, centromeres of homologues go to opposite poles
alternate
Alternate segregation leads to?
gametes with normal choromosomes
gametes with both derivatives (balanced)
In __________ segregation, next door centromeres go to the same pole
adjacent
adjacent segregation –>
abnormal segregation
Adjacent segregation is the most common form of malsegregation when…?
the translocated segments are relatively small
Adjacent segregation results in?
Trisomy and monosomy for translocated segments
What helps to determine the potential viability of zygote(s)
The size of the translocated segment - larger translocated segments offer more opportunity for recombinations
Balanced translocation carriers… risk to have unbalanced progeny?
Ranges from 0-30% depending on the type of translocation
Balanced translocation carriers
–> The risk for unbalanced progeny depends on
size of exchanged material
sex of carrier: maternal more likely to have unbalanced offspring
What are Robertsonian Translocations?
Structural chromosomal rearrangement
centric fusion
joining of two acrocentric chromosomes at the centromere, short arm
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
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
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
Human Acrocentric chromosomes
13, 14, 15, 21, and 22
Is there a risk of loss of euchromatin with Robertsonian translocations?
No, there is no euchromatin on the p arm of acrocentric chromosomes
What is the most common type of chromosomal rearrangement?
Robertsonian translocations
Is there a risk to offspring if parent has Robertsonian translocations?
Yes, risk of having unbalanced karyotype
Robertsonian translocations and fertility
Increased prevalence of RT in infertile men
Most common Robertsonian Translocation, and two other common RT
13;14 = 75% of all RTs (mos common translocation in humans)
14;21
21;21
Are Robertsonian Translocations de novo or familial?
They can be de novo or familial
De Novo unbalanced Robertsonian Translocations
If we have 46 chromosomes with normal homologue plus RT “homologue” it leads to __________
Trisomy
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)
What would be the nomenclature for trisomy 13 derived from RT (13;14) in a male?
46,XY,+13,der(13;14)(q10;q10)
What would the nomenclature be for a balanced translocation of 21 to 14 in male?
45,XY,der(14;21)(q10;q10)
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
Are familial or de novo inversions more common?
familial
Incidence of inversions?
as high as 1% in population
Inversion carriers phenotype?
Normally normal
Pericentric inversion
Inverted segment includes the centromere
break in both p and q arms
Pericentric inversion nomenclature of chromosome 9 involving break at p24 and q21? In female
46,XX,inv(9)(p24q12)
Common benign pericentric inversions in the population are called?
Heteromorphic variants
What are common heteromorphic variant pericentric inversions containing constitugive heterochromatin in the population?
9qh 16qh 1qh Yqh pericentric region of 2 or e
Benign pericentric inversion in the population containing G positive bands?
19p12
Are benign pericentric inversions familial or de novo?
Almost always familial
Are benign pericentric inversions associated wtih increased spontaneous abortions / infertility / or recombinant offspring?
No!
Which pericentric inversion is so common in the populace (2-3%) that it is no longer even reported?
9qh
report as 46,XX
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
What is the homologue pairing stage of meiosis called?
Zygotene
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
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
Recombinant 8 “rec 8”
Derived from?
inversion 8 carrier
46,XX inv(8)(p23.1q22.1)
Recombinant 8 results in two negative outcomes…
Trisomy for 8q22.1
Monosomy for 8p23.1
Rec (8) phenotype
Developmental delay
Congenital heart disease
Hypertelorism (large distance between eyes)
Thin upper lip
Inversion 8 carriers at risk for?
rec(8) offspring
Inversion 8 carrier
recurrence risk
6.7%
Inversion 8 carrier
risk for miscarriage?
not significantly increased
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
Paracentric inversion
Inversion segment excludes centromere
two breaks within the same chromosome arm
Paracentric inversion dectection?
May be more difficult to detect
Under ascertained
Are paracentric inversions familial or de novo
Familal or sporadic
Paracentric inversions and reported disease (2)
inv(11)(p13p15) aniridia (absence of iris)
Xp/q inversion and Turner syndrome anomalies
Paracentric inversions…
Abnormal meiotic products?
Either dicentric or acentric
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
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
Contiguous gene syndromes/microdeletions and microduplications are defined as?
abnormal phenotypes caused by gain or loss of a set of neighboring genes
What is del(22)q11.2
Cat eye syndrome
Example of contiguous gene Del/DUP syndrome
What are chromosome 22 rearrangements mediated by?
Segmental duplication
Cat eye syndrome is an example of
Chromosome 22 rearrangement mediated by gene duplication
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!
Wolf-Hirschorn syndrome
del(4p16.3) Facial clefting Prominent ears microcephaly intellectual disabilities
Cri du chat syndrome
del(5p15.2) microcephaly characteristic cry seizures intellectual disability
Williams syndrome
del(7q11.2)
Congenital heart disease
short stature
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)
WAGR syndrome
del(11p13) Wilms tumor aniridia genitourinary anomalies intellectual disability
Beckwith-Wiedemann syndrome
dup(11p15.5) paternal overgrowth omphalocele (gi outside) Wilms tumor other tumors
Angelman Syndrome
del(15q11-q13) maternal
seizures
intellectual disabilties
Prader Willi syndrome
del(15q11-q13) paternal hypotonia hypopigmentation hypogenitalism obesity
Miller-Dieker syndrome
del(17p13.3)
lissencephaly (no brain convolutions)
profound intellectual disability
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
