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BACKGROUND

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CHROMOSOME SPECIFIC

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Clinical Diagnosis
   

UNIPARENTAL DISOMY
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Overview

In 1980 Engel introduced the concept of uniparental disomy (UPD).  Uniparental disomy (UPD) arises when an individual inherits two copies of a chromosome pair from one parent and no copy from the other parent. Recall that normally a baby inherits one copy of each chromosome from his/her mother and one copy of each chromosome from his/ her father. In the rare circumstance of UPD a baby may have two copies of one of his/ her mother’s chromosome and no copies of that chromosome from his/ her father.  This is called maternal UPD.  Paternal UPD is when a child inherits two copies of a specific chromosome from his/ her father and no copies of that chromosome from his/ her mother.

This abnormality in inheritance may lead to health concerns in a child.  UPD can result in rare recessive disorders, or developmental problems due to the effects of imprinting.  UPD may also occur with no apparent impact on the health and development of and individual.  We will discuss the effects of UPD in greater detail, but first we must understand how UPD occurs.

Prenatal Diagnosis

  Chorionic villus sampling

   Amniocentesis

   Ultrasound

   Confined mosaicism

>Uniparental disomy

Diagnosis in blood

Preimplantation diagnosis
    How does UPD happen? 

Three possible mechanisms have been proposed for the origin of UPD:

  1. the loss of a chromosome from a trisomic zygote, "trisomic rescue"
  2. the duplication of a chromosome from a monosomic zygote, "monosomic rescue"
  3. the fertilization of a gamete with two copies of a chromosome by a gamete with no copies of the same chromosome, called gamete complementation.

All of these mechanisms require two consecutive "mistakes".

 
  UPD by Trisomic Rescue
Trisomic Rescue is the most common mechanism producing UPD. The outcome will differ depending on the timing of the original error, or non-disjunction.  For example, did the original error, which gave rise to the trisomic zygote, occur during meiosis I or meiosis II?  Review errors in meiosis I or II.  Using the diagram below to illustrate the first example, consider that both the yellow and the blue chromosomes were inherited from the egg after an error in meiosis I.  Non-disjunction in meiosis I creates a gamete with two homologous, non-identical chromosomes.  The green chromosome was inherited from the sperm.  The trisomic zygote contains three copies of the chromosome, 2 maternal copies and 1 paternal copy.  There are three equally possible options for trisomic rescue.  
  • the yellow chromosome can be eliminated, leaving the blue (maternal) and the green (paternal),
  • the blue chromosome can be eliminated, leaving the yellow (maternal) and the green (paternal), or
  • the green chromosome can be eliminated, leaving the yellow (maternal) and the blue (maternal) chromosome. 

 

  A. Trisomic rescue following an error in meiosis I.

 

In the last scenario both chromosomes are inherited from the mother, as seen in the diagram.  This is called maternal uniparental disomy (mat UPD).  The first two scenarios would lead to biparental disomy (BPD).  There is a one in three chance that a trisomic zygote which undergoes trisomic rescue will result in UPD.  Although we know that the actual genetic information is different on each of the chromosomes (the yellow one and the blue one) it is significant that they have both been inherited from the mother.  The inheritance of two homologous chromosomes from one parent is termed heterodisomy, since there are two copies of the chromosome (disomy), however the actual chromosomes are different (hetero) in genetic material.

 

Now consider the same situation of trisomic rescue, except the original imbalance in the egg was due to non-disjunction in meiosis II.  Again there are three equally possible options for loss of a chromosome.  Two would result in a biparental situation as in the previous situation, with one maternal chromosome and one paternal chromosome.  Once again, loss of the paternally inherited chromosome, represented in green, would result in uniparental inheritance.  In this situation the two blue chromosomes are very similar.  This is termed isodisomy.  "Disomy" means two copies of the chromosome and "iso" means the same. 

 

  B. Trisomic rescue followed an error in meiosis II.

 

 

UPD may cause health concerns in people for two possible reasons:

  • parental imprinting in the case of heterodisomy and isodisomy
  • the unmasking of recessive conditions in some cases of isodisomy

 

  What is imprinting?
Recall that the chromosomes are the packaging for our genetic material, our genes.  There are hundreds to thousands of genes on each chromosome.  Each gene has specific location on a chromosome.  Genes carry instructions that tell our bodies how to grow, develop and function.  Each gene gives specific instruction for the production of a particular protein which has a job in the body.  Just like the chromosomes, there are two copies of each gene, one inherited from the mother (on the maternal chromosome) and one inherited from the father (on the paternal chromosome).  Usually the information from both copies are actively being used.  When a gene actively gives the instructions to create a protein, we say that it is being expressed.  Some genes are only expressed when inherited from the father.  Other genes are only expressed when inherited from the mother.  This phenomenon of differential expression depending on the parent of origin is called imprinting.  Some chromosomes, sections of chromosomes or genes are stamped with the parent of origin.  The stamping occurs during the formation of the egg and sperm.  Imprinting occurs in each generation.  Chromosomes, sections of chromosomes or genes can be turned on and off depending on the parent from which the component was inherited.  
  • paternally imprinted genes are switched "off" when passed from father to child
  • maternally imprinted genes are switched "off" when passed from mother to child

 

  Imprinting and UPD
It is possible that concerns with imprinting may exist regardless of whether the original error occurred in meiosis I or meiosis II.  As described above, uniparental disomy is the inheritance of two copies of a chromosome from the same parent.  UPD causes concern with imprinted genes or regions of chromosomes because an individual with UPD only inherits either maternal copies of a chromosome or paternal copies of a chromosome.  In the case of paternal UPD, a chromosome may contain genes or regions that are paternally switched off.  This individual will have no working copies of these genes.  Alternatively, in the case of maternal UPD, a chromosome may contain genes or regions that are maternally switched off and this individual will have no working copies of these genes.  

Prader-Willi syndrome and Angelman syndrome provide an excellent example of the concept of imprinting.  Both conditions are the result of a deletion in the same area on chromosome 15.  If the deleted area is inherited from an individual's father the patient will have Prader-Willi syndrome (PWS).  The PWS gene is "switched off" on the maternally inherited chromosome 15, so this individual has no working copies of the PWS gene.  On the other hand, if the deleted area is maternal in origin the patient will have Angelman syndrome (AS).  The AS gene is "switched off" on the paternally inherited chromosome 15, so this individual has no working copies of the AS gene.  About 20-30% of individuals with PWS do not have a deletion, but they have inherited two maternal copies of chromosome 15, maternal UPD15.  These individuals have no paternal contribution of chromosome 15 and thus no working copy of the PWS gene.  In 1992, the first case of UPD associated with CPM was reported. A patient with Prader-Willi syndrome, cause by maternal  UPD for chromosome 15 was born after trisomy 15 was detected on CVS and a normal diploid karyotype was seen in amniotic fluid (Purvis-Smith et al, 1992). 

For further explanation and a diagram of imprinting visit the genetic imprinting fact sheet (provided by NSW Genetics Education Program)

Visit the Ledbetter & Engel Human Imprinting Map

 

  Recessive conditions

Autosomal recessive conditions are single gene disorders in which an individual must inherit two non-working copies of a gene in order to be affected with the condition.  Individuals who inherit one non-working copy are called carriers and are not affected with the condition.  In the case of isodisomy, two copies of a recessive mutation (non-working copy of the gene) can be inherited from a parent who is a carrier.  In 1988, Spence et al reported the first example of UPD in a 16-year-old female with short stature and cystic fibrosis.  Cystic fibrosis is an autosomal recessive condition.  She inherited two copies of the maternal chromosome 7 with a CF mutation from her mother who was a carrier for CF.   

Several other cases of UPD have now been determined based on the diagnosis of an autosomal recessive disease.  

 

  Clinical consequences of UPD

The type of confined placenta mosaicism (Type 1, 2 or 3), the chromosome involved and the origin of the trisomy (mitotic or meiotic), all seem to be associated with the incidence of UPD.  

There is a correlation between UPD and intra-uterine growth restriction (IUGR) and/or abnormal outcome for some chromosomes.  This may be due to adverse imprinting effects in genes that play an important role in the function of placental tissues, thereby resulting in pregnancy complications.  Since a meiotic origin correlates with both high levels of trisomy in both placental cell lineages and UPD, it is difficult to determine if an abnormal outcome associated with UPD is due to the effects of UPD itself (i.e.: imprinting effects or homozygosity for recessive traits) or to the excess of trisomy cells in the placenta and/or undetected trisomy in the fetus. 

When mosaicism is diagnosed on CVS, the incidence of UPD in a diploid fetus is theoretically 1 in 3, if the conception originally was trisomic and trisomic rescue occurred in the embryonic progenitor cells resulting in CPM.  This only applies when the trisomy is of meiotic origin and is not application for trisomies that result of somatic duplication.  

Heterodisomy is only expected to cause concern when there are imprinted genes within the region that is involved.  UPD involving most chromosomes does not cause obvious abnormalities in imprinting (Ledbetter & Engel, 1995).  However when mosaicism is found on CVS, molecular UPD testing should be considered for certain chromosomes (including 6, 7, 11, 14, 15) that are known to have adverse phenotypic imprinting effects.  Details can be found in the chromosome specific section.  Testing is available on a research basis here in Vancouver, BC Canada.  

Link to Chromosome specific section
Link to References

 

 

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