18.01.17 Segregation of structural abnormalities Flashcards
What is the frequency of autosomal reciprocal translocations?
1:500 frequency in the general population (most common structural abnormality)
How do autosomal reciprocal trasnlcoations segregate?
At meiosis I, a quadrivalent is formed to achieve maximum homology, most clearly seen in the pachytene stage of meiosis I, and therefore called a pachytene cross.
Distribution of the four homologues to two daughter cells is determined in a process known as segregation.
16 different outcomes
What are the different modes of segregation for autosomal reciprocal translocations?
2:2 segregation (6 outcomes)
Alternate – only mode leading to balanced or normal gametes (all other modes are malsegregation)
Adjacent-1 – non homologous centromeres travel together
Adjacent-2 – homologous centromeres travel together
3:1 segregation (8 outcomes)
Tertiary trisomy – 2 normal, 1 derivative
Interchange trisomy – 2 derivatives, 1 normal
4:0 segregation (2 outcomes)
Of academic interest only
How are outcomes predicted for a given translocation?
1) Draw pachytene cross roughly to scale
2) Assume alternate segregation is (a) frequent and (b) associated with phenotypic normality
3) The least imbalanced, least monosomic is most likely to produce a viable foetus
To predict the segregant outcomes for any given translocation:
Draw pachytene cross roughly to scale
Assume alternate segregation is (a) frequent and (b) associated with phenotypic normality
The least imbalanced, least monosomic is most likely to produce a viable foetus
Adjacent-1 most likely if the translocated segments are shorter than the centric ones
Adjacent-2 most likely when the centric segments are shorter than the translocated ones
3:1 most likely if one of the derivative chromosomes is small
If small segments and one small chromosome, both 3:1 and adjacent may be viable
If segments are large no mode of segregation would lead to a viable abnormal offspring
Sub-telomeric translocation may form bivalents, rather than a quadrivalent, with each pair segregating independently
What are the factors contributing to the likely viability of unbalanced translocations?
- Likely mode of segregation and viability of resulting imbalance
Large translocated segments (large imbalance) = lower risk (<5%)
Smaller segments, possibly involving microdeletion regions =intermediate risk (5-10%)
Smaller segments, possibly involving microdeletion regions, chromosomes with known syndromes, and viable products from different segregation patterns = significant risk (25-30%)
- Need to consider the particular chromosomes involved
Higher risk if chromosomes are associated with known syndromes (e.g. 13, 18, 21) or microdeletions (e.g. Wolf Hirschhorn on 4p, 1p36 deletion syndrome, Cri-du-Chat on 5p)
This may affect the most likely mode of segregation and therefore the number of viable outcomes.
Must consider UPD if regions with known imprinted loci are involved (e.g. 7, 11, 14 or 15)
- Haploid autosomal length: % HAL should be treated with caution but a rough guide of up to 2% monosomy or 4% trisomy may be viable
What is a consideration for small terminal segments at segregation?
Small, terminal translocated segments could segregate independently at meiosis without forming a pachytene cross. This is rare but high risk (as high as 50%).
How is HAL calculated?
The quantitative amount of a particular segmental imbalance can be determined as a fraction of the HAL:
Measure chromosome length (mm) from the ideogram
Measure the length (mm) of the imbalanced segment from the ideogram
Determine the % imbalance for that chromosome from the table in Daniel (1985) determine % of total HAL (found on pg500 G&S). NB, previous notes and previous edition of G&S quote the 1979 paper.
BUT does depend on chromosome. For G-band negative regions less imbalance is tolerated
Must consider genetic content of the regions and consult literature for previous cases
What is the frequency of Robertsonian translocations? What is the common feature?
1:1000 frequency in the general population
Involves the acrocentric chromosomes (13, 14, 15, 21, 22)
What are the different forms of Robertsonian translocations?
Heterologous
Homologous
How do heterologous Robertsonian translocation segregate?
Form a trivalent at meiosis to give 6 different outcomes
2: 1 Alternate - normal and carrier gametes
2: 1 Adjacent - disomic and nullosomic gametes
3: 0 very rare leading to double trisomy and double monosomy
How do homologous Robertsonian translocation segregate?
100% chance of imbalanced transmission as only two segregation outcomes:
1: 0 disomic gamete (a.k.a “1+1”:0 segregation)
1: 0 nullisomic gamete
Post-zygotic ‘trisomic correction’ could enable carrier to have a phenotypically normal child provided no UPD (so carrier of der(14;14) or der(15;15) could not have a normal child as would miscarry or be affected by UPD if trisomic correction)
Monosomic correction (conversion of a monosomic conceptus into a disomic one ) can also lead to UPD or isozygosity for a recessive gene, but this is very rare.
How do t(X;A) segregate?
In females with an X-autosome translocation:
At meiosis a quadrivalent forms
Due to X-inactivation, a greater number of conceptuses are potentially viable than in an autosome-autosome translocation, but ‘balanced’ embryos may not be ‘functionally balanced’
The ‘rules’ of segregation may not apply
In males an X-autosome translocation practically always causes spermatogenic arrest
How do t(Y;A) segregate?
Disruption of the sex vesicle and spermatogenic arrest resulting in infertility (although most common Y-autosome involves Yqh and short arm of an acrocentric and fertility is normal)
What is the phenotype for X-Y, X-X and Y-Y translocations in males and females?
Generally, a female with an X-Y translocation is usually fertile and of normal intelligence with 50% risk of having a child with the translocation.
Males with X-Y translocation is almost invariably infertile.
Pubertal and/or menstrual abnormality is the usual presentation of an X-X translocation and infertility is the rule. Y-Y translocations, just mentioned for the sake of completeness.
What is an inversion? What are the different forms?
2 break rearrangements where segment rotates 180 degrees, reinserts and breaks re-unite
Pericentric includes centromere (frequency 0.12%-0.7%)
Paracentric does not include the centromere (frequency ~0.1%-0.5%)
There are ‘normal variant’ inversions of no phenotypic consequence
Lead to reduced fertility so selected against and very rare
How do pericentric inversions behave at meiosis?
- Classically an inversion loop is formed
Cross-over outside the inversion gives normal or balanced gametes
Unequal number of crossovers within inversion gives normal, balanced and unbalanced gametes (deletion of proximal end and duplication of distal end; duplication of proximal end and deletion of distal end
- synapsis/heterosynapsis (Alternatively):
Small inverted segments: No crossing over in inverted segment, No recombinant products
Large inverted segments (b), Crossing over can occur in inverted segment, formation of recombinant products
How do paracentric inversions behave at meiosis?
If short inverted segment, meiosis probably unhindered. If large then probably loop.
Crossover outside the loop gives normal or balanced gametes
Unequal number of crossovers within, gives normal, balanced and unbalanced gametes
All recombination products are dicentric or acentric and usually lost or non-viable
What are chromosomal insertions, how common are they?
Rare, 3 break rearrangements
Inter or intra-chromosomal, direct or inverted
High risk of recombination
Inter-chromosomal frequency 1 in 80,000
How do chromosomal insertions behave at meiosis?
Inter-chromosomal
- Independent synapsing (insertional segment loops out on donor and recipient chromosomes) - most likely with small insertion
- Formation of quadrivalent - probably less common, most likely with large insertion - forms recombinant chromosomes
Intra-chromosomal: very rare, incomplete synapsis (‘looping out’) most likely - odd number of crossovers in centromeric segment will result in recombinant chromosomes
Complete synapse possible, probably only where inserted segment of large size
What are the reproductive risks associated with inter and intrachromsomal insertions?
Inter-chromosomal – up to 50% depending on the viability of the dup/del of inserted segment.
Intra-chromosomal: Risk higher for small inserted segments (20-30% up to 50%). Risk lower for large inserted segments (5-10%).
What are the reproductive risks associated with del/dups?
Theoretical risk of up to 50% of passing on deletion or duplication (gametes with deletion theoretically not viable offspring).
Assessment of risk includes genetic content, mode of ascertainment
Risk of recurrence is very small (<0.5%, G&S, 4th ed, pg 308) where de novo (Not due to parental translocation).
How frequent are ring chromosomes and how do they behave at meiosis?
Uncommon (Frequency 1 in 50,000), 99% are sporadic
At meiosis: For 46,(r) -expectation is symmetric segregation (1:1)
Note dynamic mosaicism may occur (creation of new cells with altered genetic material - ring instability)
What are the reproductive risks associated with ring chromosomes?
Risks dependent on type (full length replacing a chromosome or small supernumerary), genetic content
Observed risk for 46,(r ) parent is ~40% with offspring expected to have same, or probably more severe, phenotype than parent
For 47,+(r) carriers, each ring needs to be assessed individually
What are ESACs?
Markers/Extra structurally abnormal chromosome (ESACs)
Pathogenicity dependent on genetic content
If acrocentric short arm and peri-centromeric chromatin typically harmless
If larger with euchromatin can cause pathogenicity
Marker chormosomes can be typically small rings, small p arm isochromosomes; some lack alfa satellite DNA and form a neocentromere from existing euchromatin.
What are the reproductive risks associated with ESACs/markers?
Parental mosaicism unlikely but possible.
Risk for recurrence is less than 1%
Give two well-known examples of marker chromosomes.
- isodicentric 15; inv dup (15)
- idic(22)/ Cat Eye Syndrome
- i(12p)/ Pallister Killian syndrome
What are CCRs?
Complex rearrangements (CCRs)
Can give rise to abnormal offspring in carrier via
Malsegregation of derivative chromosomes
Generation of recombinant chromosomes (rare)
Most common CCR is a three-way exchange: Expected to form a multivalent at meiosis
What are isochromosomes?
“Mirror image” chromosome with identical arms either side of centromere
Can be more complicated (isodicentric)
Can present as supernumerary chromosome (e.g. i(12p)/Pallister-Killian syndrome)
Usually de novo
Rare cases of recurrence in siblings may reflect pre-meiotic generation in a parental gonad
