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Trisomy Disorders






In this section we begin with some background information on the early stages of growth of the zygote.

At fertilization, the egg and the sperm fuse to form a zygote with 46 chromosomes.  The single-celled zygote then enters a stage of growth called cleavage.  Cleavage produces a rapidly increasing number of cells which get progressively smaller and smaller in size.  The zygote divides through a process called mitosis.  During mitosis the 46 chromosomes make an identical copy of themselves and each pair of replicated chromosomes pull apart from each other into separate daughter cells.

The purpose of mitosis is to pass on a complete copy of genetic material to each daughter cell.  The contents of the daughter cells are identical to the original cell.  The diagram on the right illustrates typical mitosis.

In the earliest stages of growth and development the zygote divides successively to create a ball of cells, called the morula. During these early cleavages, each new cell is called a blastomere.  Each blastomere contains the identical chromosome content to the precursor cell, usually 46 chromosomes.  As the cells multiple, the morula begins to develop an inner hollow space and an inner cell mass.  This is the blastocyst stage.  

This diagram illustrates the first stages of cleavage and early cell division, from the single-celled zygote to the 64-celled blastocyst.

Mistakes can happen...

Sometimes there is a mistake in the separation or segregation of the chromosomes during mitosis.  Two sister chromatids may get "stuck together" and travel into the same daughter cell.  Or, a malfunction in chromosome sorting may find two identical chromosomes in the same daughter cell.  These errors in proper chromosome segregation are called non-disjunction.  Previously we discussed non-disjunction during the development of the sperm and the egg, which is called meiotic non-disjunction.  Non-disjunction in the zygote is called post-zygotic non-disjunction or mitotic non-disjunction.  Anaphase lag is another mechanism where one chromosome simply fails to get incorporated into the nucleus of a daughter cell.  Anaphase lag is probably the most common mechanism involved in trisomy mechanism.

Trisomy mosaicism can originate in two ways.

A. Somatic origin                      

Mitotic non-disjunction in a cell of a fertilized egg with the typical 46 chromosomes, leads to a different cell line with an additional chromosome.  Diagram A illustrates a somatic origin of the trisomy.  The cell with three copies of the chromosome may continue to grow, however the cell with only one copy of the chromosome is more often severely disadvantaged and usually will not continue to reproduce (Gardner & Sutherland, 1996). 

B. Meiotic origin

The other mechanism, which involves loss of the extra chromosome, can occur through a process called anaphase lag in an abnormal fertilized egg with 47 chromosomes.  In the process of anaphase lag, the extra chromosome fails to be included in the formation of the new cell and becomes isolated and eventually lost.  Diagram B illustrates a meiotic origin of the trisomy.

A. Somatic origin  

B. Meiotic origin  

This "mistake" in an abnormal trisomic zygote can be seen as a "correction" and is called "trisomic rescue".  If trisomic rescue occurs early in post-zygotic divisions and involves the cells destined to become the embryo, then the originally abnormal chromosome content of the fetus may be "rescued".  In both situations A and B the timing of non-disjunction greatly impacts the outcome.

Two cells lines

If an error occurs in one of the cells after fertilization it is possible to see how a baby might develop with two "lines" of cells with different chromosomal content. In this illustration, the error in mitosis occurred in one of the cells at the 4 cell stage, represented in green.

There are two possible scenarios:  

The effect on the health of the developing baby depends on the mosaic "pattern". 

The frequency of somatic origin versus meiotic origin of trisomy depends on the chromosome involved.  Somatic errors are associated with lower levels of trisomy in the body.  In general, meiotic origin is correlated with higher levels of trisomy in the body. The outcome is probably influenced by the viability of trisomic cells in the specific cell lineages (Robinson et al, 1997).

It is important to consider that the baby is derived from only a few cells (1-5 cells) from the 64-celled blastocyst.  The majority of cells at the blastocyst stage contributes to the placenta.  So, when an error occurs in a cell at the blastocyst stage it is more likely to be a cell that is destined to be part of the placenta than one destined to become the baby.

The mosaic pattern depends on many factors. 

1. Number of cells present at the time of the non-disjunction mistake

A very early mistake, as diagramed above, will effect a greater proportion of the cells in the baby.  Mosaicism originating from an early mistake, either in the first or second division of the fertilized egg, leads to generalized mosaicism, since most tissues of the baby are affected, often in a "patchy" way.   

A mistake which occurs at a later stage, for example at the 64-celled blastocyst stage, will effect a smaller proportion of the cells in the baby.  "Later errors" may lead to an abnormal line of cells confined to a certain area or tissue in the developing individual.  Theoretically, if the mistake happens just in cells that are destined to become the placenta then the abnormal cells may be confined to the placenta and may not be found in the baby.  Or if trisomic rescue occurs in the cells that are destined to become the baby, then the abnormal cells may be confined to the placenta and not found in the baby.  This is called confined placental mosaicism.  If the mistake happens just in cells that are destined to become the baby, then the abnormal cells will be confined to the baby.  This is called confined embryonic mosaicism.  Many more cells contribute to the placenta.

It is extremely difficult to diagnose confined mosaicism with certainty because it is impossible to sample all tissues in  an individual.  We will explore this in greater detail in the clinical diagnosis section.  

2. Type of cells involved

The development and health of the affected baby also depends on the type of cells affected by the mistake. The change in number of chromosomes is only important if it affects the function of the tissue(s) involved.  If the duplicated chromosome contains genetic instructions that are crucial to the function of that tissue, the effect on the overall function of the tissue might be impaired or, on the other hand, there may even be selection against the affected cells.  

3. Survival of trisomic cells

Also important in determining the outcome is the ability of the abnormal cells to survive. The question is, can the cells with the chromosome mistake continue to reproduce?  Certain mechanisms involved in cell selection may prevent the abnormal trisomic cells from reproducing, thus minimizing or eliminating the effect of the original non-disjunction error.  The specific chromosome involved seems to play a role in determining the survival of the cells. Studies of cell cultures suggest that trisomic cells generally divide less quickly and undergo cell death more commonly than diploid cells.


How is chromosomal mosaicism diagnosed?

Chromosomal mosaicism can be diagnosed in three ways:

  1. during prenatal diagnosis
  2. in an individual's blood sample or skin biopsy
  3. during preimplantation diagnosis

We have organized this section by timing of the diagnosis, which sometimes gives a clue as to how the mosaicism may impact the health of the affected individual.  Most of the concerns with chromosomal mosaicism arise when it is identified at prenatal diagnosis. Thus, most comments in this section relate to diagnosis of chromosomal mosaicism either prenatally or in early life.

How does chromosomal mosaicism affect the health of a developing baby or grown adult?

It seems likely that everyone contains some small number of cells in their body which are chromosomally abnormal

So, when does chromosomal mosaicism matter?

When chromosomal mosaicism arises during development, pregnancy outcome depends on which tissue, and how much of that tissue is abnormal.  In theory, cases with a relatively high proportion of trisomic cells are more likely to be associated with an abnormal outcome than those with a low proportion of trisomic cells.  That is, if a majority of the cells are abnormal then human development is likely to be abnormal.  If only a tiny fraction of some tissue were involved, the aneuploidy would likely have little effect on growth and development.  Perhaps many people carry a tiny and completely unimportant abnormal cell line somewhere in their body.  However, a very minor degree of mosaicism could still be important if a crucial tissue carries the abnormal cells.  For example, an abnormal chromosome change confined to one part of the brain could theoretically impair neurological function (Gardner & Sutherland, 1996).

As a general principle, an individual with a chromosome abnormality in only some of their tissues is likely to have less severe but qualitatively similar clinical features to that of someone with the non-mosaic form of the same chromosome abnormality.  For example mosaic Down syndrome can be associated with a less characteristic facial appearance and milder mental impairment than the those with typical trisomy 21.  Some chromosome changes can only exist in a mosaic form, because in a non-mosaic form they are lethal.  Sometimes if the distribution of the aneuploid cell line is assymetric, the body shape or appearance may be asymmetric.  Generally it is the cells that are aneuploid that are smaller and less developed (Gardner & Sutherland, 1996).

It is worth noting though that chromosomally abnormal cells may also arise with age and contribute to such health problems as the occurrence of cancer.  However, most age-related chromosome changes are likely either eliminated due to poor cell growth or have no obvious harmful effect.  For example, 45, X0 cells are increasingly common in female blood cells as they age, but appear to have no harmful effect.


Chromosomal mosaicism, most often involving trisomic cells (47 chromosomes) and typical cells (46 chromosomes), is detected in 1-2% of pregnancies undergoing chorionic villus sampling and in 0.1% of pregnancies undergoing amniocentesis.  Chorionic villus sampling is a prenatal diagnosis procedure which involves analysis of the chromosomes in the placenta.  Amniocentesis is a prenatal diagnosis procedure which involves chromosome analysis of cells in the amniotic fluid which are cells from the baby.  The possibility of mosaicism should be discussed with parents before any prenatal testing procedure is performed.

The clinical outcome of chromosomal mosaicism is strongly dependent on the specific chromosome involved and the number of trisomic cells in both the placenta and the baby.  When we see trisomic cells in amniotic fluid this often indicates that there are trisomic cells in the baby too.  However, the true level and distribution of trisomic cells cannot be accurately assessed with any prenatal procedure.  Therefore, ultrasound is often the best judge of how a baby is developing.  What can ultrasound look for?

What factors which should be considered when trying to predict the outcome of trisomy (or other types of) mosaicism?

1) the chromosome involved
Outcome is more serious for some chromosomes when compared to others. We explore this in detail in the section on "chromosome specific information". This is because trisomy of some chromosomes may not survive at all, unless the trisomic cells are present only in the placenta and not in the baby.  A mosaic finding on CVS or amniocentesis involving trisomy 18 or 21 is likely to have far worse implications than a mosaic finding for trisomy 15 or 16.  This is because we know that babies with trisomy 15 or 16 cells cannot survive, so if trisomy 15 or 16 is found at prenatal diagnosis it is less likely to indicate the presence of the abnormal trisomic cells in the baby.

2) the tissues affected and level of trisomy in those tissues  
In theory, cases with a relatively high proportion of trisomic cells are more likely to be associated with an abnormal outcome than those with a low proportion of trisomic cells.  Although knowing all of the tissues affected and the level of trisomic cells found in each tissue would be very helpful in predicting the clinical outcome, it is virtually impossible to determine which tissues are affected by the trisomy either prenatally or in a living person.  The only way is on autopsy, where each tissue could be analyzed.

3) method of ascertainment  
Was chromosomal mosaicism detected on chorionic villus sampling (CVS), amniocentesis, or in a sample of blood?  The way that trisomic cells were detected gives some guidance as to what tissues might be affected. For example, the presence of trisomy in CVS shows that the placenta is affected. Generally, the presence of the trisomy in amniotic fluid suggests that at least one fetal tissue may be affected by the trisomy. However, it is possible to have high levels of the trisomy in amniotic fluid with no confirmation of trisomy in blood or skin of the baby at birth.  Sometimes in cases which result in fetal death there is no evidence of the trisomy in multiple examined tissues. Likewise it is possible to have trisomy in the baby which is not detected on amniotic fluid sampling.  When abnormal cells are discovered in the blood of a living affected individual, that person will show how the presence of the cells effects growth and development.

4) ultrasound findings  
Because the outcome of trisomy mosaicism can vary widely, ultrasound often offers the best indication as to how the baby is growing and developing.  Abnormal cells tend not to grow and develop properly.
5) presence/absence of uniparental disomy  
For many chromosomes the effect of uniparental disomy is either unclear or not believed to affect the babies development. However, uniparental disomy for chromosomes 6, 7, 11, 14, and 15 can be of concern. 
6) number of previous case reports 
We often look to previous case reports to try and understand how a mosaic finding may affect an individual's health.  It is much more difficult to predict how a chromosomal change will affect a developing individual if there have only been a few reports.


Chorionic villus sampling (CVS) is an alternative to amniocentesis for prenatal diagnosis. CVS is a prenatal testing procedure offered in certain pregnancies for determination of the karyotype of the fetus.  The chorionic villi are part of the placenta.  CVS involves removing a small sample of the placenta with a thin needle which is inserted through a woman's abdomen or with a catheter which is inserted through the vagina and cervix. The location of the placenta sometimes dictates which method is used.  The procedure is carried out under the guidance of ultrasound.  In most pregnancies the chromosomal content detected in the placenta is an accurate representation of the chromosomes in the fetus.  CVS is performed at 10-12 weeks gestation.

There is a 1-2% risk of miscarriage, above the background risk, associated with the procedure.  That is, 1/100-1/50 women will lose the pregnancy following this procedure due to complications of the procedure. There is a potential risk of limb reduction defects associated with CVS of approximately 1 in 1000.

The placenta

The placenta is the connection between the mother and her baby.  It allows substances to pass from the mother to the baby and from the baby to the mother. It also produces hormones which help support the pregnancy.  The fetus and the placenta both develop from the same fertilized egg or zygote.  Thus, the chromosome content in the fetus and the placenta are usually the same.  In the earliest stages of development, the single-celled zygote undergoes multiple cell divisions.  As the cells continue to divide, some start to differentiate, that is they become programmed to develop into a certain cell type.  The first cells to differentiate are the trophoblast cells, which are destined to become part of the placenta.  The trophoblast cells are involved in implantation of the embryo in the wall of the uterus.  In the fully developed placenta, the trophoblast cells are the outer layer of the chorionic villi.  Other non-fetal cells become the villus stroma or mesenchymal core.  Here's an illustration of the placenta and the baby.

Tell me more about the development of the placenta. (more scientific details)

CVS results

The CVS sample is sent to the laboratory where it can be examined either immediately, or after the cells are cultured and allowed to grow and divide.

  1. Direct analysis is done immediately.  This type of analysis examines the trophoblast cells of the placenta.  Trophoblast cells are very rapidly dividing cells, which enables them to provide tissue to attach to the uterine wall.  This rapid division may bring on a greater vulnerability to mitotic error (Gardner & Sutherland, 1996).
  2. Cultured analysis is done on cultured cells.  This type of analysis examines the fibroblast like cells of the villus stroma or mesenchymal core found in the villus structure of the placenta.  It is thought that this method more accurately reflect the chromosomes of the fetus.  This is because the cells which become the villus stroma is more closely related to the cells which become the embryo, based on early embryonic development.

If it is not specified whether CVS was preformed on ‘direct’ or ‘cultured’ cells it usually means that cultured cells were used.

True chromosomal mosaicism is when two or more cells lines are detected in two or more culture flasks from the same individual.  Pseudomosaicism is a term used to describe two cell lines that are found in only one culture flask.  Pseudomosaicism is not concerning as it is generally a result of cultural artifact and not representative of a true finding in the baby. It is therefore not normally reported to the patient {Commentary on pseudomosaicism reporting}.

Chromosomal Mosaicism in CVS results

Approximately 1-2% of CVS results cannot be interpreted because of the presence of two cell lines in the placenta with different chromosomal complements (chromosomal mosaicism). When this happens the patient is offered the option of an additional prenatal diagnostic procedure (amniocentesis or fetal blood sampling) in an attempt to clarify the results.  

The finding of mosaicism on CVS always requires careful evaluation of the pregnancy as a whole, to try to determine if the abnormal cell line is also present in the fetus or if there is a risk of fetal uniparental disomy (Hahnemann & Vejerslev, 1997).  

The result of chromosomal mosaicism on CVS can mean one of four things:

  1. the trisomy cells are only in the placenta and there will be no harmful effect on the development of the baby or the ability of the placenta to function properly.  These pregnancies will progress normally.
  2. the trisomy cells are only in placenta and there are no genetic concerns with the development of the baby, however, the presence of the abnormal cells in the placenta impairs its ability to function properly.  Some of these babies may be small (IUGR), may be delivered prematurely, and in rare situations the impaired placenta may cause loss of the pregnancy.  Link to confined placental mosaicism.
  3. the trisomy cells are only in placental tissue and normal diploid cells are found in the baby.  However, a closer look at the chromosomes in the baby show uniparental disomy.  Uniparental disomy for certain chromosomes is associated with health concerns.  Link to uniparental disomy.
  4. the trisomy cells are both in the placenta and in the baby.  Mosaic cells in the baby have a variable effect on growth and development.

It is very important to know that an abnormal CVS result does not mean that there are trisomic cells definitely in the baby. In fact, in most cases the abnormal cells are not suspected to be in the baby or to effect the health of the baby.  This result also does not mean that there will definitely be a problem with the ability of the placenta to function. 

CVS mosaicism is a very stressful result for expecting parents.  When mosaicism is detected on CVS, couples are presented with several options to try to determine if the baby is affected; invasive prenatal options of confirming the mosaicism on amniocentesis or on fetal blood sampling.  The other option is to sample fetal skin cells at birth.


Amniocentesis is the most common test used for prenatal diagnosis of a chromosome problem in the baby.  It involves the removing a small amount of amniotic fluid which surrounds the baby in the amniotic sac. Amniocentesis is done after 15 weeks of pregnancy.  During the procedure ultrasound is used to locate the baby and the placenta.  A thin needle is inserted through the mother’s abdomen into the amniotic sac to remove some of the fluid surrounding the baby.  Within the fluid are cells which the baby has shed from its skin and bladder. The sample is taken to the lab and the baby’s cells are separated from the fluid.  The cells are grown in the lab and then examined under a microscope.  Results on the karyotype of the baby are received in two to three weeks.  There is a 0.5-1% risk of miscarriage above the background risk associated with the procedure.  That is, 1/200-1/100 women will lose the pregnancy due to complications of the procedure.

Amniocentesis results

The amniocentesis sample is sent to the laboratory where the cells are cultured (allowed to grow and divide) and then the chromosomes are analyzed.  In 12% of amniotic fluid samples that are analyzed more than one cell type is revealed (Chernos, 1994).  Usually the mosaicism is not reflective of true fetal mosaicism.  The frequency of confirmed chromosome mosaicism detected in amniotic fluid samples is about 0.1% (Bui et al, 1984).

As with CVS, true chromosomal mosaicism is when two or more cells lines are detected in two or more culture flasks from the same individual.  Pseudomosaicism is a term used to describe two cell lines that are found in only one culture flask.  Pseudomosaicism is not concerning as it is generally a result of cultural artifact and not representative of a true finding in the baby. It is therefore not normally reported to the patient {Commentary on pseudomosaicism reporting}.

Some extra scientific details of mosaicism detection: link.

Amniocentesis following an abnormal CVS result

When a couple is faced with suspected chromosomal mosaicism on CVS, amniocentesis is may be suggested. Whether amniocentesis is performed after the finding of CVS mosaicism depends on the chromosome involved and the type of chromosomal change.  In past experience, the pregnancies that most often continue to livebirth without amniocentesis are those involving aneuploidies that have been rarely described in liveborn children, even in a mosaic form, such as trisomy 2, 3 or 7.  In contrast trisomy 8, 18 and 21 only rarely continue to term without amniocentesis or fetal blood sampling (Hahnemann & Vejerslev, 1997).

When chromosomal mosaicism is not detected in amniotic fluid, the abnormal cells are thought to be confined to the placenta.  Confined placental mosaicism is not of genetic significance to the developing baby. (Goldberg & Wohlferd, 1997)  Link to confined placental mosaicism.

What does mosaicism found on amniocentesis mean?

Amniocentesis reveals a mosaic finding in 0.1% of all pregnancies.  Generally, the presence of the trisomy in amniotic fluid suggests that at least one fetal tissue may be affected by the trisomy.  However, it is possible to have high levels of the trisomy in amniotic fluid with no trisomy cells detected in blood or skin of the baby at birth.  There have also been cases in which the amniocentesis result was normal yet fetal mosaicism was present at birth (Phillips et al, 1996).

When mosaicism is detected on amniocentesis fetal blood sampling can be offered, where the expertise is available, to examine cells in fetal blood.  If the same abnormal cell line is present in fetal blood, fetal mosaicism would be confirmed.  When chromosomal mosaicism is confirmed in the fetus, a couple is presented with a very difficult situation, since fetal abnormality is not a certainty and clinical presentation may be variable.  On the other hand, if the fetal blood sampling result is normal the chance of mosaicism in the fetus is greatly reduced.  However, abnormal cells may still be present in tissues other than fetal blood.  These cases are difficult since fetal mosaicism can never be entirely excluded (Hahnemann & Vejerslev, 1997)

In either case, detailed serial ultrasound examinations may provide some reassurance if there is normal growth and no fetal anomalies detected.  


Ultrasound is a common prenatal screening test which gives a picture of the baby in the uterus by using sound waves.  These sound waves are passed through the woman’s abdomen and bounce off maternal and fetal structures to make a picture on the monitoring screen.  In an ultrasound picture, bone looks white and fluid looks black.  Show me an example of an ultrasound picture.

Ultrasound is helpful in giving some important information about the growth and development of the baby.  In early pregnancy (8-12 weeks) ultrasound can be used to find a normal heartbeat and to measure the baby to see how far along the pregnancy is.  At 18 weeks gestation, a detailed ultrasound is recommended to look for structural problems in the baby and to see if the baby is growing normally.  There are no known risks associated with ultrasound.

Tell me more about ultrasound.

Ultrasound and chromosomal mosaicism

High resolution serial ultrasound examinations are indicated when chromosomal mosaicism is detected on chorionic villus sampling or amniocentesis, in order to evaluate possible concerns with the development of the baby (Hahnemann & Vejerslev, 1997).  The findings of fetal malformation or severe growth retardation (IUGR) would be considered evidence of fetal involvement (Phillips et al, 1996).  If mosaicism is thought to be confined to the placenta, fetal surveillance through out the pregnancy is often recommended.  Normal ultrasounds are very reassuring.  

When chromosomal mosaicism is found on CVS involving the sex chromosomes, polyploidy, a marker chromosome, a structural rearrangement or the uncommon trisomies (those excluding chromosomes 13, 18 and 21) the patient can be reassured if results of the amniocentesis and serial detailed ultrasound exams are normal (Phillips et al, 1996).  However, there are limitations to what can be detected on ultrasound and for that reason a normal ultrasound reduces rather than eliminates the chance of concerns with the pregnancy.  

Some background on the origin of the placenta

The placenta is the connection between the mother and her baby.

The baby and the placenta both develop from the same fertilized egg.  Thus, the chromosome content in the baby and the placenta are usually the same.

In the very early stages in the development of the embryo, the single-celled zygote divides many times to create a ball of cells called the morula.  Each cell in the morula is called a blastomere.  Blastomeres are undifferentiated, totipotent cells.  That means that each blastomere is identical and has the potential to become any cell type in the human body.  The blastocyst develops around 4 days after fertilization as the fertilized egg travels into the uterus.  

The illustration to the left shows the structure of the blastocyst.  It is at this point that some of the cells have begun to differentiate, that is, now some are destined to become the placenta and some are destined to become the baby.  A small number of cells located on the inner part of the hollow sphere are illustrated in orange.  These 1-5 cells are called embryonic progenitor cells, and it is from these cells that the baby will develop.  The remainder of the cells in the blastocyst contribute to the placenta, also called the extra-embryonic tissue.  The outer layer of the blastocyst is made up of the trophoblast cells.  The trophoblast cells are rapidly dividing cells involved in implantation of the embryo in the wall of the uterus.  The trophoblast cells will become the outer layer of the chorionic villi, the finger-like projections of the placenta which connect the mother and the baby.  The other cells in the inner cell mass become the villus stroma.

In humans, the trophoblast cells are the first line of cells to differentiate, forming the outer cells of the morula.  The trophoblast anchors the placenta to the wall of the uterus and is responsible for exchange of nutrients and waste between mother and baby.  The proper functioning of this trophoblast tissue is likely crucial in determining if the pregnancy will continue (Robinson et al, 1997).  The inner cell mass is made up of the inner, non-trophoblast cells.  The inner cell mass cells are destined to become the mesoderm of the placenta and the few embryonic progenitor cells which will develop into the embryo itself.  

Theoretically, mitotic errors during early fetal development are more likely to occur in extra-embryonic tissue than in the cells destined to become the embryo.

Confined placental mosaicism

Confined placental mosaicism (CPM) represents a discrepancy between the chromosomal makeup of the cells in the placenta and the cells in the baby.  CPM was first described by Kalousek and Dill in 1983.  CPM is diagnosed when some trisomic cells are detected on chorionic villus sampling and only normal cells are found on a subsequent prenatal test, such as amniocentesis or fetal blood sampling.  In theory, CPM is when the trisomic cells are found only in the placenta.  CPM is detected in approximately 1-2% of ongoing pregnancies that are studied by chorionic villus sampling (CVS) at 10 to 12 weeks of pregnancy.  Chorionic villus sampling is a prenatal procedure which involves a placental biopsy.  Most commonly when CPM is found it represents a trisomic cell line in the placenta and a normal diploid chromosome complement in the baby (Robinson et al, 1997).  However, the fetus is involved in about 10% of cases (Phillips et al, 1996)

How does CPM occur?

CPM occurs in one of two ways:  

Mitotic CPM - Mitotic non-disjunction can occur in a trophoblast cell or a non-fetal cell from the inner cell mass creating a trisomic cell line in the tissue which is destined to become the placental mesoderm.  This is shown at the blastocyst level in the diagram on the right.  The blue cells represent trisomic cells.  

Meiotic CPM - Alternatively, CPM can occur through the mechanism of trisomic rescue.  If a trisomic conception undergoes trisomic rescue in certain cells, including those that are destined to become the baby, then the remaining trisomy cells may be confined to the placenta.  This is shown at the blastocyst level in the diagram on the right.  The blue cells represent trisomic cells and the white cells are normal cells.  

Several factors influence the pattern of normal and abnormal cells in the developing embryo.  Reduced or improved replication rates of the trisomic cells could effect the number of abnormal cells compared to the number of normal cells.  The  abnormal cells may fail to differentiate or function properly and could be lost.  It is also possible that there is no selection against the abnormal cells, but their presence could compromise the pregnancy on a whole. (Wolstenholme, 1996).

Types of CPM

There are three types of confined placental mosaicism depending on the cells involved at the time of the error:

What does CPM mean for a pregnancy?

Most pregnancies that are diagnosed with confined placental mosaicism continue to term with no complications and the children develop normally.  

However, some pregnancies with CPM experience prenatal or perinatal complications.  The pregnancy loss rate in pregnancies with confined placental mosaicism, diagnosed by chorionic villus sampling, is higher than among pregnancies without placental mosaicism.  It may be that sometimes the presence of significant numbers of abnormal cells in the placenta interferes with proper placental function.  An impaired placenta cannot support the pregnancy and this may lead to the loss of a chromosomally normal baby (Tyson & Kalousek, 1992).  On the other hand, an apparently normal diploid fetus may experience problems with growth or development due to the effects of uniparental disomy.  Intrauterine growth retardation (IUGR) has been reported in a number of CPM cases.  In follow-up studies adequate postnatal catch-up growth has been demonstrated, which may suggest a placental cause of the IUGR (Fryburg et al, 1993).

When predicting the likely effects (if any) of CPM detected in the first trimester, several potentially interactive factors may be playing a role, including:

Link to References


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 UPDPaternal 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

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".

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.  

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.  

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


Cytogenetic analysis of peripheral blood lymphocytes (blood cells) and/or skin fibroblasts (skin cells) are investigations which are used to determine if there is an abnormal cell line in an individual.  The finding of abnormal cells in blood and/or skin confirms the diagnosis of chromosomal mosaicism in an individual. 

In blood
Generally, when mosaicism is diagnosed on chorionic villus sampling or amniocentesis, blood sampling may be suggested either during the pregnancy (fetal blood sampling) or after the birth of the child.  Determining if the abnormal cells are found in the blood is one way of trying to determine if the abnormal cells are also present in the child.  The procedure of fetal blood sampling, involves the insertion of a needle under ultrasound guidance into the umbilical vein close to the placental insertion to obtain a fetal blood sample.  Blood sampling can be falsely reassuring, since there are cases where individuals with chromosomal mosaicism show normal chromosomes in blood and abnormal cells on skin biopsy.  

It should be noted that age at blood sampling may affect the accuracy of results.  It seems that in blood, sometimes the abnormal cells are eliminated over time.  Thus, in an individual cytogenetic analysis in infancy may reveal a higher level of mosaicism than sampling in adolescence.

Blood sampling may give a idea as to the level of mosaicism in the child.  This can further complicate genetic counselling since the clinical significance of low levels of chromosomal mosaicism found in blood is unknown.  In one case of trisomy 21 mosaicism found on blood, 5% were trisomy 21 cells and the child is reported to be developing normally at 5 years old.  In addition, the significance of mosaicism confined to a single organ is unknown (Hahnemann & Vejerslev, 1997)  Caution should be used when trying to predict outcome on the basis of percentage of trisomy cells in an infant with mosaicism.  

In skin cells (fibroblasts)
As explained above, some individuals have normal chromosomes in peripheral blood sample but are clinically affected.  Asymmetric body shape or appearance may be a sign of chromosomal mosaicism.  The distribution of the trisomic cell line, which involves generally smaller and less developed cells, can result in an assymetric appearance (Gardner & Sutherland, 1998).  An individual with mosaicism in skin cells may show variable patches of skin, such as those that are hypopigmented or hyperpigmented.  It should be noted that in skin there could be a variable distribution of the abnormal cells, thus the biopsy of one region may give only normal cells and the biopsy of another region may give abnormal cells.

The finding of chromosomal mosaicism in blood or skin may also arise on a work-up of a child who has been referred to genetics for unexplained congenital anomalies.

As mentioned previously, perhaps many of us carry a tiny and completely unimportant abnormal cell line somewhere in our body.  However, even a very minor degree of mosaicism could be important if a crucial tissue carries the abnormal cells


A preimplantation embryo is a fertilized oocyte which is undergoing early post-zygotic cell divisions as it travels down the fallopian tube into the uterus.  The embryo implants in the wall of the uterus at the 64-cell blastocyst stage.

Review pictures of the early cell divisions.

There is a very high rate of mosaic aneuploidy in the two to eight cell-stage human embryo.  In a study of 250 embryos by Almeida & Bolton (1996) the overall incidence of chromosomal abnormality was 49%.  Studies show that there is progressive loss of chromosomally-abnormal embryos during preimplantation development (Almeida & Bolton, 1996) and the preimplantation embryos with a larger proportion of aneuploid cells are the ones less likely to survive to implantation.  There is evidence of early cell selection factors which select diploid cells over trisomic cells for survival in the developing embryo

Preimplantation genetic diagnosis (PGD) is a procedure of embryo biopsy performed on the oocyte/zygote, cleavage stage embryo, or blastocyst.  Most centres currently perform the biopsy at the cleavage stage .  Single-cell diagnosis is performed by the polymerase chain reaction (PCR) or fluorescent in-situ hybridization (FISH) (Harper & Delhanty, 2000).  The high prevalence of mosaicism persisting to the blastocyst stage pose problems for PGD.

Clinical outcome specific to each chromosome

Predicting the clinical presentation of chromosomal mosaic individuals is very difficult.  In this section, we have tried to summarize what is known about the effects of mosaicism for each chromosome.  Looking at published case reports, there is often a broad range of clinical outcomes reported, even when the same chromosome is involved.  It is important to recognize that the cases that are published may not accurately reflect the frequency of possible outcomes.  There is generally a tendency to publish cases with the worst outcomes or unusual presentations, thus neglecting the less severe, more ordinary and often more frequent outcomes.   Since there is little systematic data about clinical outcome, this section can only be considered a guide to patients and families.  This section is reliant on our own judgment and interpretations of the data rather than proven facts.

It is not our intention to encourage patients and families to try to predict their own outcome.  We encourage you to browse the whole web site to gain an understanding of how chromosomal mosaicism occurs and why there is so much variability in expression of these conditions.  We hope that you use this section to get an idea of the kind of health conditions certain individuals diagnosed with chromosomal mosaicism have experienced. 

The contents of this section

For each chromosome we will review some of the relevant cases reports in the literature, discuss the occurrence of confined placental mosaicism and the potential implications of uniparental disomy.  We will mention concerns that may arise in prenatal diagnosis.  This section is more medically focused and may provide detailed information and medical terminology which is not aimed at the general public.  

All pages provide links to information and support groups relevant to each specific chromosome.  A list of references is provided at the bottom of each page with links to the abstracts in PubMed for more details on the case reports and studies cited. 

As you are browsing through this section it is important to remember that the great majority of pregnancies with chromosomal mosaicism detected on chorionic villus sampling proceed uneventfully and result in normal live born infants.


Trisomy of chromosome 1 is very rare. Trisomy 1 conceptions have not been observed in the large case reports of chromosomal mosaicism discovered in the placenta or the fetus during prenatal diagnosis (Hsu et al, 1997, Hahnemann & Vejerslev 1997).   There is one report of a spontaneous pregnancy loss which was found to have trisomy 1 with no fetal development (Hanna et al, 1997).  

Trisomy 1 conceptions most likely die before implantation and therefore may occur in preimplantation embryos but are not seen during prenatal diagnosis (Field et al, 1998).

There are, however, cases of mosaicism involving supernumerary marker chromosomes containing chromosome 1 material (and thus partial trisomy 1) (Rothlisberger et al. 2001)

Uniparental Disomy (UPD 1)

Pulkkinen et al. (1997) and Field et al (1998) each reported a case of maternal UPD1.   Gelb et al. (1999), Takizawa et al. (2000), Thompson (2002) and  Rivolta et al. (2002) each reported a case of paternal UPD1.  These cases were all discovered through rare recessive conditions.  In no cases were there features indicative of imprinting, suggesting there are no imprinted genes on chromosome 1 with major phenotypic effects (Field et al, 1998).   Three additional cases have since been reported, including one case also mosaic for a supernumerary marker chromosome (Rothlisberger et al. 2001).

Based on the case reports UPD1 is thought to be harmless (i.e. imprinting effects are excluded).

Link to What is UPD?
Link to Maternal UPD 1 page
Link to Paternal UPD 1 page

Internet Links


Field LL, Tobias R, Robinson WP, Paisey R, Bain S. (1998) Maternal uniparental disomy of chromosome 1 with no apparent phenotypic effects. American Journal of  Human Genetics 63:1216-20. PubMed

Gelb BD, Willner JP, Dunn TM, Kardon NB, Verloes A, Poncin J, Desnick RJ (1998) Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis. American Journal of  Human Genetics 62:848-854  PubMed

Hahnemann JM, Vejerslev LO. (1997) Accuracy of cytogenetic findings on chorionic villus sampling (CVS)—diagnostic consequences of CVS mosaicism and non-mosaic discrepancy in centers contributing to EUCROMIC 1986-1992. Prenatal Diagnosis 17(9):801-20  PubMed

Hahnemann JM, Vejerslev LO (1997) European Collaborative Research on Mosaicism in CVS (EUCROMIC):fetal and extrafetal cell lineages in 192 gestations with CVS mosaicism involving single autosomal trisomy. American Journal of Medical Genetics 70:179-187  PubMed

Hanna JS, Shires P, Matile G (1997) Trisomy 1 in a clinically recognized pregnancy. American Journal of  Human Genetics 68:98  PubMed

Hsu LY, Yu MT, Neu RL, Van Dyke DL, Benn PA, Bradshaw CL, Shaffer LG, Higgins RR, Khodr GS, Morton CC, Wang H, Brothman AR, Chadwick D, Disteche CM, Jenkins LS, Kalousek DK, Pantzar TJ, Wyatt P. (1997) Rare trisomy mosaicism diagnosed in amniocytes, involving an autosome other than chromosomes 13, 18, 20, and 21: karyotype/phenotype correlations. Prenatal Diagnosis 17(3):201-42.  PubMed

Ledbetter DH, Engel E. (1995) Uniparental disomy in humans: development of an imprinting map and its implications for prenatal diagnosis. Human Molecular Genetics 4:1757-1764  PubMed

Pulkkinen L, Bullrich F, Czarnecki P, Weiss L, Uitto J (1997) Maternal uniparental disomy of chromosome 1 with reduction to homozygosity of the LAMB3 locus in a patient with Herlitz junctional epidermolysis bullosa. American Journal of  Human Genetics 61:611-619 PubMed

Rivolta C, Berson EL, Drya TP (2002)  Paternal uniparental heterodisomy with partial isodisomy of chromosome 1 in a patient with retinitis pigmentosa without hearing loss and a missense mutation in the Usher syndrome type II gene USH2A.
Arch Ophthalmol. 2002 Nov;120(11):1566-71  PubMed

Rothlisberger B, Zerova TE, Kotzot D, Buzhievskaya TI, Balmer D, Schinzel A (2001) Supernumerary marker chromosome (1) of paternal origin and maternal uniparental disomy 1 in a developmentally delayed child. J Med Genet 38:885-888

Takizawa Y, Pulkkinen L, Chao SC, Nakajima H, Nakano Y, Shimuzu H, Uitto J (2000) Mutation report: complete paternal uniparental isodisomy of chromosome 1: a novel mechanism for Herlitz junctional epidermolysis bullosa. J Invest Dermatol: 115(2) 307-11

Thompson DA, McHenry CL, Li Y, Richards JE, Othman MI et al. (2002) Retinal dystrophy due to paternal isodisomy for chromosome 1 or chromosome 2, with homoallelism for mutations in RPE65 or MERTK, respectively. Am J Hum Genet 70:224-229






























This website has been developed to provide information to patients, families, health care providers, students and the general public on the unique conditions of chromosomal mosaicism.   We have tried to create an easy-to-navigate, comprehensive website of interest for those both with or without a scientific background and to provide in-depth coverage of specific abnormalities.  

Please note, that while we are happy to provide the information in this website to you, we cannot give out medical advice over the internet. We feel that it is important to preserve the health care provider-patient relationship. However, please feel free to refer your health care provider to our site and the references herein. 

We are very interested in learning of new cases of prenatally detected mosaicism and hearing of pregnancy outcomes. More about our research can be found on our lab website.


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