Cytogenetic Abnormalities and Recurrent Miscarriage

Question 1

Approximately what percentage of recognised pregnancies will miscarry?

Answer 1

About 15-20% of recognised pregnancies will miscarry.

Question 2

Approximately what percentage of women will have 2 or more miscarriages?

Answer 2

About 2-5% of women will have 2 or more miscarriages.

Question 3

Approximately what percentage of miscarriages are thought to be chromosomally abnormal?

Answer 3

It is thought that at least 50% of miscarriages are chromosomally abnormal.

All autosomal trisomies have been reported in spontaneous abortions. Common examples are trisomy 16, 21 and 22.

Question 4

What percentage of Patau syndrome (trisomy 13) pregnancies will miscarry?

Answer 4

95%

Question 5

What percentage of Edward syndrome (trisomy 18) pregnancies will miscarry?

Answer 5

95%

Question 6

What percentage of Down syndrome (trisomy 21) pregnancies will miscarry?

Answer 6

80%

Question 7

What is the empirical recurrence risk for a couple after a pregnancy with autosomal trisomy?

Answer 7

About 1%

Question 8

What may be the explanation if a particular trisomy recurs in a couple?

Answer 8

If a particular trisomy recurs in a couple then there may be a risk of gonadal mosaicism.

Question 9

Approximately what percentage of couples experiencing recurrent early miscarriages (3 or more) will carry a balanced rearrangement?

Answer 9

Approximately 5% percent of couples experiencing recurrent early miscarriages (3 or more) will carry a balanced rearrangement?

Question 10

Why do miscarriages often occur in couples that carry a balanced rearrangement?

Answer 10

Miscarriage occurs because the balanced rearrangement is passed on in unbalanced form (the balanced rearrangement mal-segregates) to the egg or sperm thus resulting in a genetically unbalanced conception.

Question 11

What are the most common types of balanced chromosomal rearrangements?

Answer 11

1) . Translocation - balanced exchange between two chromosomes.
2) . Inversion - segment of a chromosome inverted.
3) . Insertion - a section of one chromosome is inserted into another.

Question 12

Describe a balance reciprocal translocation.

Answer 12

Some genetic material from one chromosome is exchanged with another chromosome in a reciprocal translocation. The translocation carrier is usually normal but they may experience recurrent pregnancy losses and could have abnormal offspring.

Question 13

Describe Robertsonian translocations.

Answer 13

A Robertsonian translocation can be described as ‘effectively balanced’ and carriers are usually clinically normal. They are described as effectively balanced because a Robertsonian translocation results from the fusion of the the centromeric regions of two acrocentric chromosomes (13, 14, 15, 21, 22). They usually have only 45 chromosomes and have lost the short arms of the two acrocentric chromosomes involved (the short arms of acrocentric chromosomes generally contain only non-coding DNA). If chromosome 21 is involved then the carriers have an increased risk of having children with Down syndrome.

Question 14

Why may males with a Robertsonian translocation have disrupted sperm production?

Answer 14

Robertsonian translocated chromosomes need to form trivalents during meiosis if meiosis is to be able to progress. Successful pairing of trivalents does not always occur. In a number of meiotic cells the pairing will fail. Non-pairing during meiosis disrupts meiosis. A male carrier of a Robertsonian translocation will often have a reduction in sperm production and may experience fertility issues. Even if sperm production is successful a number of the sperm will be unbalanced and would result in abnormal offspring were they to fertilise a partner’s egg.

Question 15

Describe chromosomal inversions.

Answer 15

Balanced carriers of chromosomal inversions are usually normal. However, they could have reproductive problems including reduced fertility and a small possibility of producing live born abnormal offspring. There is only a risk of having abnormal offspring if the inverted segment is big, includes the centromere and the end sections are very small.

There are two types of chromosomal inversions:

1) . Pericentric inversion - centromere is within the inverted segment.
2) . Paracentric inversion - the inverted segment occurs in one or other arm and the centromere is unaffected.

Question 16

What conditions are usually required of a chromosomal inversion for there to be a risk of the production of abnormal offspring?

Answer 16

There is only a risk of having abnormal offspring if the inverted segment is big, includes the centromere and the end sections are very small.

Question 17

What is a paracentric inversion?

Answer 17

Paracentric inversion - the inverted segment occurs in one or other arm and the centromere is unaffected.

Question 18

What is a pericentric inversion?

Answer 18

Pericentric inversion - centromere is within the inverted segment.

Question 19

How do chromosomes containing pericentric inversion pair up during meiosis?

Answer 19

During meiosis an inversion loop is formed as this is the only way that the homologous regions of the two chromosomes can synapse during meiosis.

If a recombination event occurs within the inversion loop formed in a pericentric inversion carrier then 50% of the meiotic products will be unbalanced.

50% of the cells produced will be either normal or balanced inverted chromosomes whereas the other 50% will carry one or other of the recombinant products.

The recombinant products will either consist of a duplication of the distal p arm region beyond the break point with a p arm at both ends of the chromosomes and the q arm segment deleted, or vice versa.

(either recombinant chromosome dup p distal or recombinant chromosome dup q distal).

Question 20

What can happen if a recombination event occurs within the inversion loop formed in a pericentric inversion carrier?

Answer 20

If a recombination event occurs within the inversion loop formed in a pericentric inversion carrier then 50% of the meiotic products will be unbalanced.

50% of the cells produced will be either normal or balanced inverted chromosomes whereas the other 50% will carry one or other of the recombinant products.

The recombinant products will either consist of a duplication of the distal p arm region beyond the break point with a p arm at both ends of the chromosomes and the q arm segment deleted, or vice versa.

(either recombinant chromosome dup p distal or recombinant chromosome dup q distal).

Question 21

How do chromosomes containing paricentric inversion pair up during meiosis? What will the products of recombination be?

Answer 21

Like with pericentric inversions an inversion loop will form in order that all the homologous segments can pair successfully.

Assuming a recombination event has occurred within the inversion loop 2/4 of the meiotic products will be normal or balanced. The other 2 products will be recombinant and abnormal.

The recombinant chromosomes formed from a paracentric inversion are extremely unbalanced and are very unlikely to be seen at term (or even towards the later stages of the pregnancy).

The 2 recombinant products are:

1) . A dicentric chromosome - dicentric chromosomes usually fail to divide successfully at any subsequent mitotic divisions because the 2 centromeres tend to get pulled apart so they tend to be lost during mitosis.
2) . An acentric chromosome - an acentric chromosome has no centromere at all and will be lost very quickly at any subsequent mitotic divisions.

Generally speaking, carriers of balanced paracentric inversions are not considered to have an elevated risk of live born abnormal offspring. They don’t usually even have an increased risk of miscarriage because any pregnancies lost occur very early. The most likely effect is slightly reduced fertility.

Question 22

Do carriers of balanced paracentric inversions have an increased risk of having live born abnormal offspring?

Answer 22

Generally speaking, carriers of balanced paracentric inversions are not considered to have an elevated risk of live born abnormal offspring. They don’t usually even have an increased risk of miscarriage because any pregnancies lost occur very early. The most likely effect is slightly reduced fertility.

Question 23

What is considered to be the rarest group of balanced chromosome rearrangements?

Answer 23

Balanced insertions.

Question 24

Describe balanced insertions?

Answer 24

An insertion consists of 3 break points, 2 break points within one arm of one chromosome. The segment defined by those 2 break points is then inserted at a single break point within the other chromosome.

Carriers of balanced insertions are usually normal. However, they can have quite a high risk of having abnormal offspring with either deletions or duplications of the chromosome section that is found inserted and carried in another chromosome.

Question 25

What type of balanced chromosome rearrangement presents the highest risk to a carrier of having a live born abnormal offspring?

Answer 25

Balanced insertions.

Question 26

How many break points are involved in a balanced chromosome insertion?

Answer 26

An insertion consists of 3 break points, 2 break points within one arm of one chromosome. The segment defined by those 2 break points is then inserted at a single break point within the other chromosome.

Question 27

Describe the problems that may be experienced by balanced chromosome rearrangement carriers?

Answer 27

Most balanced carriers are usually clinically normal. If they are not clinically normal then they may have a de novo translocation with the breakpoint disrupting a gene. If they are clinically normal, they may well have reproductive problems such as recurrent miscarriages, abnormal unbalanced babies, and primary or secondary infertility issues.

Question 28

Why is it important to carry out segregation analysis when a balanced translocation is detected?

Answer 28

It is important to carry out segregation analysis whenever a balanced translocation is detected because it is important to be able to provide the carrier of that rearrangement some information as to whether they have any risk of having a live born unbalanced offspring, miscarriages etc. so that they can make an informed decision as to whether they want PND in any future pregnancies.

Balanced carriers can always be reassured that they do have a good chance of having normal or balanced children.

Question 29

How does a reciprocal translocation behave at meiosis?

Answer 29

Normally at meiosis the homologous chromosome pairs form a bivalent which are paired along the entire length of the chromosome pair.

If you have a reciprocal translocation however then 4 different chromosomes from 2 homologs share common sequences. In order for those chromosomes to pair effectively across all homologous sequences a quadrivalent has to be formed.

The 4 chromosomes involved in the quadrivalent will then segregate to the two daughter cells which form the gametes. The chromosomes may segregate in a 2:2 ratio, a 3:1 ratio, or a 4:0 ratio. However, 4:0 segregation can usually be disregarded as products are usually inviable.

Question 30

Describe how you may go about carrying out a segregation analysis for a reciprocal translocation.

Answer 30

In order to carry out a segregation analysis it is helpful to draw the shape of the quadrivalent as best you can to scale in terms of the size of the segments that have been exchanged.

Draw the homologous centromeres on the horizontal axis.

Question 31

Describe the 3 possible ways that a 2:2 segregation could occur during meiosis involving reciprocally translocated chromosomes.

Answer 31

There are 3 possible ways that a 2:2 segregation could happen. The first example is called alternate segregations.

1). Alternate segregation - as you travel around the quadrivalent each centromere will segregate to alternate daughter cells. Alternate segregation always results in balanced carrier or normal offspring.

Another example of a 2:2 segregations is called adjacent 1 segregation. There are 2 types of adjacent segregation in which adjacent chromosomes in the quadrivalent segregate together.

2) . Adjacent 1 segregation - in adjacent 1 segregation the non-homologous adjacent centromeres segregate together. Adjacent 1 segregation always results in an imbalance.
3) . Adjacent 2 segregation - again this involves adjacent chromosomes from the quadrivalent which segregate together but in this case the homologous centromeres segregate together. Adjacent 2 segregation always results in imbalance.

Question 32

True or false? Alternate segregation always results in balanced carrier or normal offspring.

Answer 32

True.

Question 33

Describe alternate segregation.

Answer 33

Alternate segregation - as you travel around the quadrivalent each centromere will segregate to alternate daughter cells. Alternate segregation always results in balanced carrier or normal offspring.

Question 34

What is adjacent segregation?

Answer 34

Another example of a 2:2 segregations is called adjacent 1 segregation. There are 2 types of adjacent segregation in which adjacent chromosomes in the quadrivalent segregate together.

2) . Adjacent 1 segregation - in adjacent 1 segregation the non-homologous adjacent centromeres segregate together. Adjacent 1 segregation always results in an imbalance.
3) . Adjacent 2 segregation - again this involves adjacent chromosomes from the quadrivalent which segregate together but in this case the homologous centromeres segregate together. Adjacent 2 segregation always results in imbalance.

Question 35

Will adjacent 1 segregation result in a balanced daughter cell?

Answer 35

Adjacent 1 segregation always results in an imbalance.

Question 36

What type of adjacent segregation results in homologous centromeres segregating together?

Answer 36

Adjacent 2 segregation - again this involves adjacent chromosomes from the quadrivalent which segregate together but in this case the homologous centromeres segregate together. Adjacent 2 segregation always results in imbalance.

Question 37

What type of adjacent segregation results in non-homologous centromeres segregating together?

Answer 37

Adjacent 1 segregation - in adjacent 1 segregation the non-homologous adjacent centromeres segregate together. Adjacent 1 segregation always results in an imbalance.

Question 38

Describe how 3:1 segregation occurs.

Answer 38

In 3:1 segregation 1 daughter cell receives 3 chromosomes from the quadrivalent whereas the other daughter cell receives 1. There are 4 possible options of 3:1 segregation because any 3 chromosomes can segregate together (any 1 chromosome can segregate on its’ own).

3:1 segregation always results in an imbalance.

There are 2 possible options which are known as:

1) . Tertiary trisomy/monosomy
2) . Interchange trisomy/monosomy

1) . Tertiary trisomy results in a daughter cell which, if fertilised to form a conception, will cary 47 chromosomes (trisomy) and the additional chromosome is structurally abnormal. The tertiary monosomy carries the 1 remaining chromosome from the quadrivalent so if fertilised will give you a conception with only 45 chromosomes and will be missing a normal chromosome and have a structurally abnormal chromosome in place of the other chromosome involved in the translocation.
2) . Interchange trisomy/monosomy is the other form of 3:1 segregation. In this case the interchange trisomy daughter cell if fertilised produces a conception with 47 chromosomes but both halves of the chromosome interchange are present in that conception and the additional chromosome is an additional normal chromosome (have in effect the balanced 2 halves of the translocation plus 1 normal extra chromosome). The interchange monosomy is missing a normal homolog and carries none of the normal structurally abnormal chromosomes.

Question 39

Describe the results of tertiary trisomy/monosomy in 3:1 segregation.

Answer 39

Tertiary trisomy results in a daughter cell which, if fertilised to form a conception, will cary 47 chromosomes (trisomy) and the additional chromosome is structurally abnormal.

The tertiary monosomy carries the 1 remaining chromosome from the quadrivalent so if fertilised will give you a conception with only 45 chromosomes and will be missing a normal chromosome and have a structurally abnormal chromosome in place of the other chromosome involved in the translocation.

Question 40

Describe the results of interchange trisomy/monosomy in 3:1 segregation.

Answer 40

Interchange trisomy/monosomy is the other form of 3:1 segregation. In this case the interchange trisomy daughter cell if fertilised produces a conception with 47 chromosomes but both halves of the chromosome interchange are present in that conception and the additional chromosome is an additional normal chromosome (have in effect the balanced 2 halves of the translocation plus 1 normal extra chromosome). The interchange monosomy is missing a normal homolog and carries none of the normal structurally abnormal chromosomes.

Question 41

What can you do to visualise the form of segregation that will give you the least imbalance?

Answer 41

Draw a line down the 2 longest arms of the quadrivalent cross.

The segregant that gives you the least imbalance is likely to be the most viable in terms of live born viable offspring and is thus the most worrying outcome in terms of risk of having abnormal live born offspring.

Question 42

What is the only viable product for t(11;22)(q23;q11)?

Answer 42

The tertiary trisomy for the derivative 22 is the only viable product reported for t(11;22)(q23;q11).

Since male carriers rarely transmit a 3:1 segregant female carriers have a higher risk than male carriers.

This is a well documented translocation with a significant risk to female carriers and prenatal diagnosis should be offered (for reassurance if the carrier is male).

If a male carrier is detected then any female relatives of that male should be tested.