Williams syndrome is not a disease. It cannot be caught and it cannot be cured. It's something that is uniquely part of the individual. The characteristics and medical issues that present themselves in Williams syndrome (WS) are directly related to a set of missing genes on the 7th chromosome. Williams syndrome is considered a microdeletion, which means a small section of genes are missing from one of the person's chromosome. The number of missing genes can vary but the classic deletion is close to 25.
The typical person contains 23 sets of chromosomes. Each chromosome is made up of tightly wound DNA, which codes for everything in your body. How your body looks, how it grows, how it works from day to day and even how it acts- are all determined by genetics. DNA is really a blueprint or map that your body uses to make proteins. Proteins are the workers of your body. You need them to build body structures and to accomplish tasks. Without them, your body simply doesn't function like it should. This is why a small deletion of 25 genes out of thousands can make such a huge impact on how a person's body works- like in WS.
Williams syndrome is caused by a totally random genetic mishap. It is not something that runs in families and the only way it can be passed on to future children is if the person with WS has children, which we'll get to later. The likelihood that this takes place is around 1 in 12,000. This number is relative and changes as we better understand and diagnose the disorder. Something to consider, however, is that everyone has the same chance of this happening. Even those who have a child with WS have the exact same odds when they have another child. Again, the only situation where this changes is when a person with WS has children.
There is some research that has suggested that some people have an inverted section of DNA just above the WS region that increases the likelihood that the deletion will occur. This only makes the odds 1 in 9,000 so it is still very unlikely. In fact, it's so unlikely that most insurance companies will not pay for parents of children with WS to have genetic testing completed before having future children.
How a deletion occurs
When a mother and father create sperm and eggs (gametes), their bodies manipulate the chromosomes to increase diversity in a process called meiosis. It all starts with a cell that contains a complete set of 46 chromosomes (23 different types, each with a matching pair). These chromosomes are duplicated or copied by the cell to make a total of 92 chromosomes. When they are duplicated something called crossing over occurs. Crossing over is essentially rearranging a stack of blocks. One of your chromosomes may have a "green block" where the other has a "yellow" so crossing over basically trades them so the stacks look a little different.
Crossing over is the step in meiosis where a small deletion could take place. Sometimes, a group of genes will "stick". For example, chromosome A made a trade of about 10 genes with chromosome B. But, when chromosome B made the trade, another 25 genes stuck to the original 10. So now, chromosome A has 25 extra genes (called a duplication) and chromosome B has 25 less (called a deletion).
What genes are missing?
This is a big question, partly because it depends on the person. We call the "classic deletion" to include 25-28 genes, because most individuals with WS are missing this amount. Some people, however, may have had more genes "stick" during crossover, and others may have had less "stick" so they may be more or less respectfully. Another reason this is a tricky question is because we're still trying to figure that out. Researchers have not identified what all these genes do and how their disappearance affects the body, so it's hard to say exactly what is missing.
This is what we do know. The genes are missing from the 7q11.23 portion of the chromosome. This means that it's on a portion of the long arm of the 7th chromosome. Here is a list of some of the genes we know are affected:
- Elastin: The main gene that we use to genetically diagnose Williams syndrome is called ELN or elastin. This gene is missing in 99% of individuals diagnosed with WS. Elastin is a well understood protein that is used to make up connective tissue. This tissue is designed to stretch when an organ, like blood vessels or skin need to adjust in size. When this gene is missing it causes a variety of issues in the heart and vessels and skin, to name just a few.
- LIM- Kinase1: We also know that most with WS are missing the LIM-kinase1 gene. This gene is associated with our ability to see an object and mentally assemble all the parts into a whole- which is called visual spacial ability. The absence of this makes it difficult for someone to draw and write.
- CLIP2: This gene sequence is used by the nervous system to make proteins that build neurons which are nervous system cells. It forms the skeleton of the cell, giving it shape and structure. It is not entirely known how this affects individuals with WS, but many think it has a large effect on the WS behavior profile and issues of WS that affect the nervous system.
- GTF2IRD1 gene: This gene is somewhat of a supervisor over other genes. It activates and deactivates the production of proteins by other genes. This has control over many nervous system functions and the structure of muscle and bones, particularly in the face. The deletion of this gene contributes to the characteristic facial features of a person with WS, issues with the formation and position of the teeth and difficulties with fine muscle movement such as writing and drawing.
- GTF2I gene: This gene is known to participate in immune function in the brain. It controls the release of a chemical that causes cell growth and division, especially in the likelihood that a cell comes in contact with viruses and bacteria. The absence of this gene in WS has evidence to cause dental abnormalities and has a role in the visual-spatial issues that make writing and drawing difficult.
- STX1A gene: This gene allows nerves to communicate with one another using chemicals called neurotransmitters. In WS, the absence of this gene may be the cause of lower IQ.
- BAZ1B gene: This gene is involved in repairing DNA mistakes when body cells divide. It also helps make the structural backbone of chromosomes and is involved in the body's regulation of vitamin D. The absence of this gene has been shown in research to lead to low body weight, dental abnormalities and lower bone density.
- NCF1 gene: This gene regulates the body's control of hypertension or high blood pressure. Interestingly, if a person is missing this gene, they are less likely have high blood pressure. This gene is on the end of the WS section so some people may not be missing it.
How do we diagnose WS?
Before the 1980's, Williams syndrome was only diagnosed by a physician that knew what they were looking for. This diagnosis was based on facial features, behavior profile and related medical conditions. In today's age, we know that was probably pretty unlikely that a pediatrician would know about WS, so it was considered a rare condition (the ratio was 1 in 20,000 at the time). In the 1980's, the field of genetics became more advanced and a better test became available. It is called fluorescence in-situ hybrid testing or FISH testing for short.
FISH testing uses a probe or marker that is attracted to and binds to a specific sequence of DNA. A blood sample is taken from the patient and chromosomes are separated so a photograph can be taken. The chromosome sample is mixed with a fluorescent dye that is designed to stick to the ELN or elastin gene. Then a picture is taken of the chromosomes under a black light. This causes the area to glow where the dye sticks. In a typical person without WS, they would have two areas glowing in the picture since we have two copies of ELN, one on each chromosome. In a person with WS, they will only have one glowing chromosome, since the other is missing that sequence. This confirms the diagnosis of WS.
FISH testing has its good and bad points. Good being it has increased the diagnoses of people with WS because it can give a definitive answer with 99% accuracy. This is why over the past 30 years, the odds of having WS have increased. This doesn't mean that WS is more common today than before. It just means we have a better way of diagnosing the disorder than we once had. There were a lot of people walking around prior to the 1980's with no clue that they had WS. The other benefit of FISH testing is that it's very inexpensive so it is generally covered by insurance. It can be tested with a blood sample, again easy to obtain, and it's quick to provide results. The family will get results within 2-4 weeks.
The drawbacks to this type of testing is that it doesn't give you any more information other than that you have one or two copies of the ELN gene. Many parents will be left with unanswered questions as far as how many genes are missing. Naturally parents are going to wish for this information so they will know what to expect. Within the past few years a new way of diagnosing genetic abnormalities has emerged called a microarray. This test will actually map out many genes in a person's genome and tell a geneticist if there is one copy (deletion), two (typical) or three (duplication) copies of each gene. This is more valuable information because it tests many genes rather than only one. It is more expensive, however, and most people who qualify for this type of testing are part of research studies for having multiple genetic conditions in addition to WS. Overtime, however, it's possible that this will become the standard in genetics testing. As it is used more often, it will most likely become less expensive and more mainstream.
So what does this mean for my child's future?
Individuals with Williams syndrome have greater odds of having a child with WS than the general population. Although deletions are a random occurrence in nature, there is one situation where it can be passed on genetically- if a person with WS has a child. Once that deletion is part of your genetic make-up, it will become a part of half the eggs or sperm that the person creates during the same meiosis process explained earlier. Therefore, half of the eggs, for example, in a woman with WS will have a typical chromosome and half will have the deletion. So, if a woman with WS has children, the likelihood that their child will have WS is 50%.
Many people wonder about what would happen if a male with WS has a child with a female with WS. This can be solved using a simple Punnet square.