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
