Trisomy Disorders

Posts Tagged ‘genetic disorder

Noninvasive method accurately and efficiently detects risk of Down syndrome

February 2012

Using a noninvasive test on maternal blood that deploys a novel biochemical assay and a new algorithm for analysis, scientists can detect, with a high degree of accuracy, the risk that a fetus has the chromosomal abnormalities that cause Down syndrome and a genetic disorder known as Edwards syndrome. The new approach is more scalable than other recently developed genetic screening tests and has the potential to reduce unnecessary amniocentesis or CVS. Two studies evaluating this approach are available online in advance of publication in the April issue of the American Journal of Obstetrics & Gynecology(AJOG).

Diagnosis of fetal , or aneuploidies, relies on invasive testing by chorionic villous sampling or amniocentesis in pregnancies identified as high-risk. Although accurate, the tests are expensive and carry a risk of miscarriage. A technique known as massively parallel shotgun sequencing (MPSS) that analyzes cell-free DNA (cfDNA) from the mother’s plasma for fetal conditions has been used to detect trisomy 21 (T21) pregnancies, those with an extra copy of chromosome 21 that leads to , and trisomy 18 (T18), the chromosomal defect underlying . MPSS accurately identifies the conditions by analyzing the entire genome, but it requires a large amount of DNA sequencing, limiting its clinical usefulness.

Scientists at Aria Diagnostics in San Jose, CA developed a novel assay, Digital Analysis of Selected Regions (DANSR™), which sequences loci from only the chromosomes under investigation. The assay requires 10 times less DNA sequencing than MPSS approaches.

In the current study, the researchers report on a novel statistical, the Fetal-fraction Optimized Risk of Trisomy Evaluation (FORTE™), which considers age-related risks and the percentage of fetal DNA in the sample to provide an individualized risk score for trisomy. Explains author Ken Song, MD, “The higher the fraction of fetal cfDNA, the greater the difference in the number of cfDNA fragments originating from trisomic versus disomic [normal] chromosomes and hence the easier it is to detect trisomy. The FORTE algorithm explicitly accounts for fetal fraction in calculating trisomy risk.”

To test the performance of the DANSR/FORTE assay, Dr. Song and his colleagues evaluated a set of subjects consisting of 123 normal, 36 T21, and 8 T18 pregnancies. All samples were assigned FORTE odd scores for chromosome 18 and chromosome 21. The combination of DANSR and FORTE correctly identified all 36 cases of T21 and 8 cases of T18 as having a greater than 99% risk for each trisomy in a blinded analysis. There was at least a 1,000 fold magnitude sepa

In a related study, researchers from the Harris Birthright Research Centre for Fetal Medicine, Kings College Hospital, University of London and the University College London Hospital, University College London, provided 400 maternal plasma samples to Aria for analysis using the DANSR assay with the FORTE algorithm. The subjects were all at risk for aneuploidies, and they had been tested by chorionic villous sampling. The analysis distinguished all cases of T21 and 98% of T18 cases from euploid pregnancies. In all cases of T21, the estimated risk for this aneuploidy was greater than or equal to 99%, whereas in all normal pregnancies and those with T18, the risk score for T21 was less than or equal to 0.01%.

“Combining the DANSR assay with the FORTE algorithm provides a robust and accurate assessment of fetal trisomy risk,” says Dr. Song. “Because DANSR allows analysis of specific genomic regions, it could be potentially used to evaluate genetic conditions other than trisomy. The incorporation of additional risk information, such as from ultrasonography, into the FORTE algorithm warrants investigation.”

Kypros H. Nicolaides, MD, senior author of the University of London study, suggests that fetal trisomy evaluation with cfDNA testing will inevitably be introduced into clinical practice. “It would be useful as a secondary test contingent upon the results of a more universally applicable primary method of screening. The extent to which it could be applied as a universal screening tool depends on whether the cost becomes comparable to that of current methods of sonographic and biochemical testing.”

Dr. Nicolaides also notes that the plasma samples were obtained from high-risk pregnancies where there is some evidence of impaired placental function. It would also be necessary to demonstrate that the observed accuracy with cfDNA testing obtained from the investigation of pregnancies at high-risk for aneuploidies is applicable to the general population where the prevalence of fetal trisomy 21 is much lower. “This may well prove to be the case because the ability to detect aneuploidy with cfDNA is dependent upon assay precision and fetal DNA percentage in the sample rather than the prevalence of the disease in the study population,” he concludes.



Introduction to Chromosome Diseases

Chromosome diseases are genetic diseases where a large part of the genetic code has been disrupted. Chromosomes are long sequences of DNA that contain hundreds or thousands of genes. Every person has 2 copies of each of the 23 chromosomes, called chromosomes 1..22 and the 23rd is the sex chromosome, which is either X and Y. Men are XY and women are XX in the 23rd chromosome pair.

Causes of chromosome diseases: Chromosomal diseases arise from huge errors in the DNA that result from having extra chromosomes, large missing sequences, or other major errors. These are usually caused by a random physical error during reproduction and are not inherited diseases (i.e. both parents are usually free of the condition).

Spontaneous chromosome errors: Most chromosomal diseases arise spontaneously from parents where neither has the disease. A large genetic mistake typically occurs in the woman’s egg, which may partially explain why older women are more likely to have babies with Down syndrome

Many chromosome errors cause the fetus to be aborted before birth, but some syndromes can be born and survive, though all typically suffer severe mental and physical defects. Down syndrome  is the
most common and well-known chromosome defect, but there are many.

Types of chromosome diseases: There are several common types of chromosome errors that cause disease. The effects of errors in the sex chromosomes (X and Y) differ greatly from errors in the autosomes (chromosomes 1..22).

The following major classes of chromosome diseases can occur:
*    Trisomy conditions: Most people have 2 copies of each chromosome, but some people are born with 3 copies, which is called trisomy. Trisomy can occur in chromosomes 1..22 (autosomal trisomy) and also in the sex chromosome (see below). Down syndrome  is a
trisomy affecting the autosome chromosome 21.
*    Monosomy conditions: When a person has only one of a given
chromosome, rather than a pair, this is called monosomy. These conditions are very rare for autosomes (chromosomes 1..22) because body cells without pairs do not seem to survive, but can occur in the sex chromosome (monosomy X is Turner syndrome.
*    Sex chromosome conditions: Typically men are XY and women are XX in the pair for the 23rd chromosome. However, sometimes people are born with only one sex chromosome (monosomy of the sex chromosome), or with three sex chromosomes (trisomy of the sex chromosome).

Rarer types of chromosome diseases: There are also some other rarer types of chromosome conditions that may lead to diseases:
*    Translocation disorders: Partial errors in chromosomes can occur,
where a person still only has a pair, but accidentally has entire sequences
misplaced. These can lead to diseases similar to trisomy. For example,
Translocation Down Syndrome is a subtype of Down
Syndrome caused by translocation of a large sequence of a chromosome. *    Subtraction disorders: The process of translocation can also cause
large sequences of DNA to be lost from chromosomes. This creates diseasessimilar to monosomy conditions.
*    Mosaicisim: This refers to the bizarre situation where people have
two types of cells in the body. Some cells have normal chromosomes, and somecells have a disorder such as a trisomy.
*    One-sided chromosome disorders: For these unusual diseases it
matters whether the chromosomes were inherited from the father or mother. 

Non-contagiousness of chromosome diseases: All types of genetic diseases occur at birth including chromosome diseases. You cannot catch the disease from someone else who has the disease. You are either born with the error in your chromosomes or not Genetic tests can determine whether or not a person has a chromosome disease, even as early as in the fetus by antenatal testing  for genetic diseases.

Sex Chromosome Conditions
Sex chromosome defects: There are various defects of the sex chromosomes. Normally a man has XY and a woman XX. But the wrong combinations can arise with extra sex chromosomes or missing ones:
*    Turner syndrome  (XO syndrome, monosomy X, missing Y): This should just be called the “X syndrome” because the person has an X, but no second sex chromosome. Such people are female, as there is no male Y chromosome. It is a 1-in-5000 syndrome, involving some relatively minor conditions, but usually sterility.
*    Klinefelter syndrome (XXYsyndrome, also rarely XXXY): a 1-in-1000 disorder where the person is usually male (because of the Y chromosome), but has lower levels of testosterone and may have some female-like features (because there are two X chromosomes), and is usually sterile. The rarer XXXY syndrome may lead to retardation.
*    Jacobs syndrome  (XYY syndrome): The person has an extra Y male chromosome. He will be male and may be largely
normal, or may suffer from minor features such as excess acne and may be very tall, and in some cases behavioral complaints such as aggression.
Frequency around 1-in-2000.
*    Triple-X  (XXX, also XXXX or XXXXX): These people are females with an additional X chromosome. In rarer cases, there can even be 4 or 5 X chromasomes. They can be largely normal, or may suffer from problems such as infertility (some but not all), and reduced mental acuity. Occurs with a frequency around 1-in-700.

Note that there is no ordering, and XYX would be the same as XXY.
So there are viable combinations: XX (male), XY (female), XXY (Klinefelter), XXX, XYY, and XO (Turner). They all contain the X chromasome. Interestingly, there has been no combinations found that contain only Y: YO (Y, missing X), YY, or YYY syndromes. Not even aborted fetal embryo cells with this combination have been found. It has been suggested that there is something fundamental on the X chromasome that is needed for life.

Autosomal Trisomy Chromosome Diseases
The 22 non-sex autosome chromasomes (autosomes) can also exhibit disorders, of which the most common is trisomy (having 3 copies rather than a pair). Because these are disorders of the autosomes and not the sex chromasomes, these disorders can occur with males or females.

These chromosome diseases arise rather surprisingly from an extra copy of the DNA, which makes you wonder why having 3 copies of the code bad even when the DNA code on the extra chromosome is actually correct. The condition of having 3 chromosomes is called trisomy and the most common example for autosomes is Down syndrome.

Here is some details about particular autosome disorders:
*    Down syndrome (trisomy 21): an extra autosome creating a triplet at chromsome 21. These people are usually mentally retarded, and have physical characteristics such as an enlarged tongue and rounded flattened facial features. Frequency is around 1-in-800 but risk increases with the age of the mother to around 1-in-25 for a 45-year-old mother. The extra chromasome occurs because the mother’s egg (or less commonly father’s sperm) has wrongly kept both of its autosome 21 pair.
*    Edwards syndrome (trisomy 18): an extra autosome at chromasome 18. Most fetuses are aborted before term, but a live birth with this condition occurs with a frequency around 1-in-3000. Edwards syndrome is more severe than Down’s syndrome, and includes mental
retardation and numerous physical defects that often cause an early death.
*    Patau syndrome (trisomy 13): a very
severe disorder leading to mental retardation and physical defects,
occurring with a frequency around 1-in-5000. It is so severe that many
babies die soon after birth.  Miscarriages caused by trisomy: So we have seen trisomies at autosomes 13, 15, 18, and 21. Trisomy at the other autosomes seems to be fatal in embryos leading to spontaneous miscarriage. The high frequency of natural miscarriages, around 1-in-5, occurs to a large extent because of chromasome errors.

Causes of trisomy: Since Down syndrome occurs more frequently in older women, one might theorize of the reason why. The most likely idea is that the problem is not during the pregnancy, but at the start, with more eggs created with poorly separated chromasomes in older women (about 1-in-5 for young women, compared to 3-in-4 for 40-year-old women). However, another possibility is that the female body gradually loses its ability to recognize wrong cells in a fetus. But it is not an immune issue because the uterus is an immune-privileged site during pregnancy.

Partial trisomy: Down syndrome can be caused not only by a full trisomy, but also by a partial trisomy at autosome 21. Due to errors in a process called “translocation”, a part of a chromasome can be wrongly attached to another pair. This creates a partial trisomy.
Another possible variant of Down’s syndrome is a translocation between two pairs of chromasomes, usually part of 21 gets add to the 14th. This also causes a variant known as Translocation Down syndrome.

Mosaicism: Yet another chromosome oddity is mosaicism, where a person has different sets of chromasomes in different cells. If some cells are normal and others have trisomy 21, then Down syndrome results. Mosaicism can result from two paths. In the first method, the fetus started with trisomy 21, and then one line of cells lost the trisomy. In the second method, the fetus started normal, but somehow a cell line gained trisomy 21.

So why chromasome 21? It is one of the smaller chromasomes, and has
relatively few genes (maybe 200-250). Research continues into determining why having too many of these genes, and consequent gene overexpression, leads to Down syndrome’s characteristic mental and physical features.

Monosomy and Autosome Subtraction Disorders
Monosomy occurs when there is only one of a pair of chromosomes and is usually non-viable. For example, the opposite of Down syndrome is
monosomy-21, which is fatal. More common are “subtraction disorders” which occur due to missing genetic material within chromosomes, typically when a sequence of a chromosome is missing. The creation of reproductive sperm and egg cells involves a complex process that can sometimes misplace parts of a chromosome, such that one cell has an extra sequence (perhaps leading to one of the trisomy disorders if this cell becomes a child), but if a child is generated from the other cell, it may get a subtraction disorder.
*    Cri-du-chat syndrome  (cat’s cry): a subtraction disorder at autosome 5, with a missing short arm of chromasome 5, but not an entirely missing chromasome. Extremely rare at 1-in-50,000 and exhibiting severe mental retardation and physical defects including larynx problems giving the characteristic cat-like child’s cry.
*    Prader-Willi Syndrome (PWS)
and Angelman Syndrome: These are two separate genetic chromosome subtraction disorders that arise from the deletion of the same sequence on one copy of chromosome 15, specifically the sequence are “15q11-13”. Prader-Willi Syndrome arises when it occurs on the father-inherited copy of chromosome 15, and Angelman Syndrome occurs if from
the mother-inherited copy. This one-sided distinction between the father and mother’s chromosomes is unusual, and quite important, and is discussed in detail later.

One-sided genetic disorders: Prader-Willi Syndrome and Angelman Syndrome. There are several disorders that have an odd characteristic in that it actually matters which of a pair of chromosomes is affected. Different effects arise for the chromosomes from the mother and from the father. This was a totally unexpected discovery since traditional genetic theory, particularly the “law of equivalent crosses”, indicated that it did not matter which chromosome a gene was present on. However, it seems that the body does distinguish between the chromosomes that come from the father and the mother within each pair. Some genes are only activated on the chromosome that came from the mother’s or father’s side. It is like having male and female genes with slightly different effects. They are “imprinted” with some extra information, although exactly how this occurs is as yet unclear.

The best known examples are Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS), which both arise from the same sequence on chromosome 15. They are both rare, arising around 1-in-10,000 to 1-in-15,000 but the two diseases are related in a surprising way. For some reason, the sequence 15q11-13 is likely to be misplaced during reproductive cell creation. Rather than causing a single disease, this error can cause two diseases. If it is deleted from the mother’s egg, the child will get Angelman Syndrome; if the deletion occurs in a father’s sperm, the child gets Prader-Willi Syndrome.

It is also important to note that both Prader-Willi and Angelman are
actually gene disorders, not really chromosome disorders. Although the most common cause is from chromosome deletion (a non-inherited random physical occurrence), both of these diseases can arise rarely from a non-chromosome genetic inheritance. The real cause of the disease is the missing genes, rather than the chromosome-level changes.

The gene for Angelman has been identified as the gene that creates the E6AP ubiquitin protein ligase 3A (UBE3A) protein, which is involved in the ubiquitination pathway (whatever that is). Inherited mutations of the UBE3A gene do cause Angelman without any major chromosome error. The exact gene for PWS is not known since there are several genes on the 15q11-13 sequence deleted in PWS and AS. The most
likely PWS gene seems to be SNRPN (small nuclear ribonucleoprotein N) gene but it is not yet certain.

PWS and AS are very distinct diseases. They are not two variants of the same disease and have significantly different mental and physical features. This makes sense since they are caused by failures of different genes. The AS gene is mother-sided and the gene(s) causing PWS are father-sided.  PWS has several features, the most notable of which is a total lack of appetite suppression leading sufferers to continual hunger and over-eating. If left uncontrolled, they will literally eat themselves to death via extreme obesity and the consequent heart or organ damage. PWS suffers may have a slightly reduced mental capacity, but are not usually significantly retarded. Other physical features include some facial features, hypogonadism (testes or ovaries), and short stature.
AS is a more several mental disorder causing retardation or at least
developmental difficulty. There are usually speech problems and an
inappropriately happy smiling child.  AS is caused by one gene only, despite losing several genes in chromosome deletion. Presumably, the other missing genes are compensated for by the genes on the other chromosome in the pair, but for some reason the AS gene
is one-sided and cannot be activated on the father’s chromosome. The UBE3A gene is only one-sided within brain cells, which explains why AS is a mental disease without physical defects. The UBE3A gene is expressed from both chromosomes in other tissues.

Because AS is a single gene disease, there are in fact several ways to get
*    Chromosome deletion (most common): loss of the 15q11-13 sequence on the mother’s copy of chromosome 15, which deletes the UBE3A gene (and many others as well).
*    Uniparental disomy: getting both copies of chromosome 15 from the
father (i.e. the pair), so there is no mother’s copy of chromosome 15 at
*    Gene mutations: ordinary localize genetic mutations within the UBE3A gene, causing AS in the same way as other genetic non-chromosome diseases. However, the mutation only causes the disease if on the father’s chromosome copy. A mutation in UBE3A on the mother’s side does not cause AS, nor does it cause PWS, since PWS and AS involve different genes.
*    Imprint disorders: mutations in the genetic code that surrounds the
gene, inhibiting the activation of the UBE3A gene. Another point to note is that both male and female children equally get AS and PWS. The one-sided gender-imprinting of the gene is not affected by the gender of the child with the disease.

Does one-sidedness go back to the gender of grandparents? Must it comes from the mother’s mother or father’s father, or can it cross gender in the previous generation?

Some traits inherited from only one side? The one-sidedness of these
diseases also raises the question of what other traits are inherited from
only one parent.

Uniparental disomy: Another strange way to get both PWS or AS is called uniparental disomy. This means getting from one parent (uniparental) both pairs of chromosome (disomy). In a pair, you get two chromosomes from one parent, none from the other. Although the majority of PWS and AS are caused by simple deletions within a chromosome, some cases arise because both copies of chromosome 15 come from the same parent. Somewhere along the path, the egg or sperm kept both of its pair of chromosome 15, and the other
parent’s copy was discarded. People with two mother-inherited copies of
chromosome 15 get PWS and two father-inherited copies cause AS.
Uniparental disomy is interesting because the person theoretically has two good copies of chromosome 15 with no genes missing. However, it doesn’t work that way. For full health, you need copies from both parents.

Also interesting is that having the entire chromosome 15 from the mother’s side seems to only cause PWS, despite there beinghundreds or thousands of genes on the entirety of chromosome 15. Hence, it would seem that very few genes are one-sided. If lots of genes are one-sided, then numerous diseases would arise from uniparental disomy of chromosome 15 rather than just one.  Note that uniparental disomy has been seen on several chromosomes: 4, 6, 7, 11, 14, 15, 16, and 21. Like trisomy, it also occurs more often for an older mother.

One-sided disease genes compared to X-linked recessive carriers: But how is this different from X-linked recessive disorders? Isn’t inheriting
Prader-Willi as an error from the mother’s side the same as inheriting a
recessive hemophilia gene from a mother carrier? The answer is no, not
really, there are several differences. Firstly, the gender differences in
hemophilia arise because it involves a gene on the X sex chromosome, whereas one-sided genes occur on autosomes. Secondly, although X-linked recessive disorders are similar to a maternal one-sided disorder, there is no analogous X-linked or autosomal recessive inheritance pattern that matches paternal one-sided disorders.


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