Williams syndrome (WS) is a rare genetic disorder that is caused by a microdeletion (1.5-1.8-Mb ) on the long arm of chromosome 7 (7q11.23 to be precise). The deletion affects approximately 28 genes, one of them being the gene ELN which codes for elastin in our body. However, there is no single gene in the pathogenic variants that causes WS.

 

I am no expert in genetics, nor do I have a medical degree, but I have worked with parents and children with WS for over 15 years and  below are some questions parents often have when their child received a diagnosis for WS. So I will try to answer these questions to the best of my ability, using my experience of working with WS and the research out there.

 

How can WS be diagnosed?

WS is diagnosed genetically as well as clinically.

In the past WS was genetically diagnosed by a Fluorescence In Situ hybridization (FISH) test which involved taking a sample of blood from the child and inserting two probes, a control probe and a probe that reacts with ELN. The probe is a very small chemical that glows brightly when it detects a specific element on a chromosome. A scientist uses a special microscope to look at the chromosome and see how many bright spots are present. When a person has a WS deletion, only one bright spot for ELN can be seen  instead of two (one on each chromosome) but two spots appear for the control probe. These days a chromosomal microarray is used to genetically diagnose WS which scans either the entire genome or targeted regions of the genomes to detect copy number variants (losses or gains of chromosome material), which may be benign, pathogenic, or of uncertain clinical significance. 

 

Clinically, WS is diagnosed when the following features are present: cardiovascular disease (especially SVAS or narrowing of arteries), distinctive facial features (broad forehead, short nose, wider nasal tip, wide mouth, thick lips, small chin), Connective tissue abnormalities (Hoarse voice, inguinal/umbilical hernia, bowel/bladder diverticulae, rectal prolapse, joint limitation or laxity, and soft, lax skin), cognitive delay, growth abnormalities (especially failure to thrive and poor weight gain in infancy) and endocrine abnormalities (including hypercalcemia and hypothyroidism).

 

What caused the deletion?

To put it simply: during the time chromosome 7 was duplicated, something went wrong and a section of the chromosome was not duplicated correctly. It is not caused by something that parents did or did not do. This also explains why the incidence of WS (about 1 in 20,000 life births) does not vary depending on country.

 

Why are parents tested when their child receives a diagnosis of WS?

In most cases parents are not affected at all. Yet, when the child receives a diagnosis of WS, parents are often asked to be tested as well. I always wondered why this is the case. Well, we all have variations in our genetic make-up, especially inversions where the genetic material is there but in a different order. About 6% of people have an inversion on the same region of chromosome 7 as WS but this inversion is considered typical. Yet, 25% of parents who have a child with WS have this typical inversion which is much higher than what is expected for the general population. As a parent with the inversion has 50% chance of passing on this inversion to their child, parents are asked to be checked in case they want to have future children. It is argued that parents who have the inversion might be more likely to have another child with WS. Yet, this is extremely rare (you are more likely to win the lottery) and has only been reported in 3 cases. However, if people with WS have children than these children have 50% chance of having WS as well. So, please rest assured, most parents who have a child with WS and have the inversion have other children who do not have WS.

 

My child has a smaller deletion does this mean my child will be affected less?

 

It has been argued, especially on the WSA website that: “The size of the deletion plays a role in the symptoms of WS. Individuals who have a deletion of 28 instead of 26 genes are less likely to have hypertension. Deletions longer than 28 genes are associated with more severe intellectual disability, and seizures (infantile spasms). Deletions shorter than 26 genes are associated with fewer symptoms which vary depending on what genes are deleted. “

Although I am no expert in this field, I would like to put these strong claims within the right context.

1)    There is no direct relationship between genes and behavioural outcomes. We are all the product of our development, that includes our environment, the people we grow up with, the opportunities we have had, whether we have been hospitalised for a long time, etc. All of these factors will have an influence on who we become and what we can achieve.

2)    These claims are based on studies with small sample sizes and mainly included adults with WS. However, these studies did not take development into account or how these individuals might have differed from each other.

3)    Genes interact with each other and thus, it is not only the size of the gene deletion that matters but also which genes are deleted. However, we do not know much about how genes interact with each other and thus, making conclusions about genes and behaviour from the size of the genetic deletion alone may well be incorrect.

4)    Yes, from a scientific point of view analysing the relationship between the size of the deletion in WS and the outcome can be useful in order to further our understanding about what each gene in our body does. However, from a practical and clinical point of view we need to be very careful with the conclusions that are being made from these studies (see my point about development and outcome).

 

Hope this has helped a little.