Chromosomal Abnormalities

Original article by Tom Leach | Last updated on 15/12/2014
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Chromosomal abnormalities are a very common cause of spontaneous miscarriage. Most commonly a child with a chromosomal abnormality will not survive to birth. However, there are many cases where the child will survive, although often they have severe disability in life.

  • The normal rate of miscarriage in the general population is 15%. Miscarriage does not become statistically significant unless one particular woman has >3 instances.
  • Another common cause of miscarriage is a balanced translocation in one parent
 

Chromosome facts

  • 15-20% of all pregnancies end in miscarriage – 50% of these cases are a result of chromosomal abnormality.
    • 10% of sperm have a chromosome abnormality
    • 25% of oocytes have a chromosomal abnormality
  • Only around 1% of live births has a chromosomal abnormality
    • This is about 5% in still births
 

Definitions

  • Aneuploidy – an inappropriate number of chromosomes/copies of one particular chromosome (can be greater or fewer than normal)
  • Trisomy – the existence of 3 copies of a particular chromosome
 

Types of chromosome

Chromosomes can be divided into three physical categories, depending on the location of their centromere
    
 
 
 

Metacentric – these are chromosomes with two long arms, and a centromere in the middle

 
 
 
 

 

 

 

Submetacentric – these are chromosomes with a long arm and a short arm

 

 

 

 

Acrocentric – these are chromosomes with only long arm. On the other side of the centromere are ‘satellites’ that contain little genetic information, usually related to the production of ribosomes. This genetic info is generally repeated elsewhere in the genome and is not fundamental.

 
 
 
 

Reciprocal Translocations

In these cases, there is an exchange of genetic material between chromosomes.
 

Balanced Reciprocal Translocations

  • 1 in 500 people has a balanced reciprocal translocation.
  • Typically, cases are unique to a particularl family, but a balanced translocation with chromosomes 11 and 22 is also a common occurrence.
In these cases, the total amount of genetic material remains the same (hence the name ‘balanced’). There is a breakage of two chromosomes, and the material that breaks off is exchanged between the two. In a very small number of cases the ‘break point’ where the original chromosome breaks can involve a functional gene. This can result in learning difficulty in those affected.
  • Reciprocal translocations can often only be identified with FISH, particularly if the broken segments are of equal length.
 

Unbalanced reciprocal translocations

In these cases, the total amount of genetic material is not conserved. They can arise de novo, or also from the behaviours of a balanced reciprocal translocation in one of the parents, dueing meiosis.

At meiosis, a balanced reciprocal translocation may not be able to pair up correctly. Instead of paring in ‘two’s’ with the other same number chromosome, the balanced translocation ends up pairing in fours; known as a pachytene quadrivalent. In such a situation, all the genetic material matches up with its opposing genetic material, but because each chromosome has information from 2 chromosomes, they group in a four:

 
This is important when the chromosomes separate into gametes: there are four possible outcomes:
This above separation is known as a 2:2 outcomes. It is also possible to get a 3:1 outcome at separation, whereby 3 of the chromosomes stick together, creating a gamete with 2 lots of chromosomal info (and thus likely to produce a triploidy in the offspring), and one gamete that is lacking the info of one chromosome.
 
Unbalanced translocation can result in phenotypic signs, typically:
  • Developmental delay
  • Learning difficulties
  • Congenital defects
Parents of children with an unbalanced translocation should be tested to see if they are carriers or if the mutation was de novo. Carriers will have a risk of having another affected baby. In such cases, amniocentesis could determine whether future children also carry the defect.
 

Robertsonian Translocations

aka centric fusion
  • Robertsonian translocations can occur in any of the acrocentric chromosomes. These are the chromosomes that have a long arm and no short arm, and include numbers 13, 14, 15, 21 and 22.
  • In a Robertsonian Translocation, the satellites are lost, and the long arm of one chromosome fuses with the long arm of another acrocentric chromosome. This reduces the total number of chromosomes to 45.
  • The satellites code for ribosomal RNA, but so do the satellites on all acrocentric chromosomes, so in a Robertsonian translocation, there is little genetic significance – unless the translocation affects meiosis. 
  • Robertsonian translocations occur in 1 in 1000 individuals in the general population, and usually the long arms of 13 and 14 fuse, to create 13q14q.
  • Down’s syndrome is the major clinical effect of robertsonian translocations. Other effects that occur as a result of meiosis in the presence of a robertsonian translocation will either result in a balanced translocation with no clinical effects, or monosomy / trisomy of any of the acrocentric chromosomes, which will result in miscarriage.
 

Deletions

This is where part of a chromosome is lost. Usually it is the terminal end of the chromosome that is lost, but loss of other parts can occur.
Typically, they can only be seen on FISH. Examples include:
  • DiGeorge’s Syndrome - widely varying clinical effects even with familial cases. Results in congenital defects, typically cleft lip and palate, congenital heart problems and sometimes also learning difficulties. There may also be a weakened immune response.
    • Due to a deletion at 22q11.
  • William’s Syndrome – again may result in learning difficulties, although individuals are often cheerful, and very friendly, especially to strangers. May have abnormal facial appearance.
    • Due to a deletion at 7q11
  • Cri du chat syndrome – so called due to the meow like cry that babies with this condition are affected with. Children may also have difficulty feeding and talking (due to small pharynx and larynx) as well as developmental problems.
    • Due to a deletion on chromosome 5p