18.01.17 Segregation of structural abnormalities Flashcards Preview

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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?

1. 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%)

2. 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)

3. 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?



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?

1. 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

2. 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?


1. Independent synapsing (insertional segment loops out on donor and recipient chromosomes) - most likely with small insertion

2. 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.

1. isodicentric 15; inv dup (15)
2. idic(22)/ Cat Eye Syndrome
3. 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