Originally posted 4 June 2015
Last updated 16 September 2023
Available in Portuguese http://pmsbrasil.org.br/entendendo-o-tamanho-da-delecao/
Probably everyone living with 22q13 deletion syndrome knows that it is much more than a disease of the brain. My son, David, is not unusual in that regard. He has flaky toenails, gastrointestinal (GI) problems, and poor temperature regulation. 22q13 deletions affect the entire body. I worry about painful conditions that he is unable to express to me (see Can 22q13 deletion syndrome cause ulcerative colitis?) or other medical condition that may shorten his life. That said, as parents we primarily see our child’s future most influenced by his intellectual disability: the loss of typical cognitive development. What causes this defining feature of 22q13 deletion syndrome?
Terminal deletions
Somewhere around 95% of individuals identified with 22q13 deletion syndrome have terminal deletions, where the chromosome has a piece broken off the end. About 10% of the deletions are inherited (unbalanced translocation), but the rest are not (de novo). The remaining individuals have interstitial deletions: the broken and missing material is somewhere inside the chromosome without affecting the end of the chromosome. 22q13 deletion syndrome was not originally associated with a single gene. But, disruptions of the SHANK3 gene became included under the umbrella name “Phelan-McDermid syndrome” (abbreviated as PMS) or “Phelan-McDermid deletion syndrome” (PMSD). The term PMS has been used inconsistently, sometimes excluding interstitial deletions and sometimes not. For a long time I avoid using the PMS name (see 22q13 deletion syndrome – an introduction). There is another reason to omit discussing single gene mutations (properly called “pathogenic variants”) when discussing a contiguous chromosomal deletion syndrome like 22q13 deletion syndrome. Single gene variants can have very funny and unpredictable effects. See my explanation (Gene deletion versus mutation: sometimes missing a gene is better). A variant can have no effect (benign), it can be a weak effect because we normally have two of each gene, or it can have a very strong “dominant negative” effect. A dominant negative means that the variant gene is worse than losing the gene altogether. Thus, variants of a gene like SHANK3 may have different effects, but the individuals with SHANK3 variants may not be representative of most people we know who have 22q13 deletion syndrome. Most of the people identified with PMS have a chromosomal deletion syndrome. There is important overlap, but there are also important differences. This article discusses chromosomal deletions rather than SHANK3 variants.
Even small terminal deletions cause a major loss of genes
What most people do not understand about chromosome 22 is that the 22q13 area is rich in genes near the terminal end. That is, deleting a small part of the end removes a lot of important genes. Here is a chart based on the most complete published study to date (Sarasua et al., 2014) and the most complete listing of genes available.
(Right click on the graph and open to a new window to see it full size.)
The graph has two lines drawn across the 22q13 region of the chromosome. The scale on the bottom is distance from the end of the chromosome. Zero is the terminal end of the chromosome (the end of the DNA). The numbers 1 through 12 are the distance in megabases (Mb) from the terminal end. Thus, small deletions are on the left, larger deletions are on the right.
The line in blue, shows how many people have a deletion of at least a certain size. The scale on the left shows the percentage of the population. For example, about 97% of documented cases of 22q13 deletion syndrome have deletions that are 1 Mb in size or larger (red arrow at 1 Mb). People with very small deletions are actually uncommon. It is far more common to find people with 1 Mb deletions or larger. In green, you can see how many genes are involved with each deletion size. The thick red arrows show that the same 97% of cases are missing a whopping 25% of the known genes in this region of the chromosome. The green line jumps up rapidly in the first 1 Mb. After the green line jumps up, it flattens out for a long stretch of the chromosome. From a genetics standpoint, people with 2, 3 or even 4 Mb deletions are not very different from people with 1 Mb deletions. So, 22q13 deletion syndrome is a syndrome of many genes for most people.
This chart also helps explain why the effects of deletion size have confused people (including scientists) for so long. There are so few cases of small deletions and so many genes, that researchers have never been able to tease out how individual genes contribute to the disorder (although many claims have been made). It has been confusing to families that deletion size does not easily explain difference among their children. Here we see one reason. Deletions smaller than 1 Mb are rare and terminal deletions between 1 and 4 Mb add very few additional genes. It makes sense given the shape of the green line. About 30% of the population has essentially the same size deletion.
You might ask, what kind of genes are in the “gene rich” 1 Mb part of the chromosome? Are they important to the hallmark trait of 22q13 deletion syndrome, intellectual disability (cognitive dysfunction)? The answer is a resounding, yes! There are 31 genes in the first 1 Mb and 10 of these are related to brain function. Thus, 97% of 22q13 deletion syndrome patients are missing 10 or more “brain genes”. An investigation into which PMS genes are the most likely to cause problems after a deletion narrows this list and provides a roadmap for research (see Which PMS genes are most important?). Genes likely to affect IQ are mapped in detail in this blog PMS, IQ and why interstitial deletions matter.
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Andy,
You are doing a great job. Really enjoyed this.
Curtis
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Roger,
It is special praise coming from such a clinical expert on 22q13 deletion syndrome. Thank you.
Andy
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My 2 year old son is suspected of having phelan-mcdermid syndrome. we are waiting for the results. I’m terribly scared. there is very little information in Poland. I would like to ask if there is a chance that the baby will talk. Are there cases where adults live quite independently? does it always regress? thank you very much for any information
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Paula
The Phelan-McDermid Syndrome Foundation (pmsf.org) has information that will be helpful. I understand your fear. I can answer your questions. Yes, there is a chance that your child will talk. Some children talk fluently. Some have only a few words and phrases. Some use an electronic device. My son does none these, but we usually know what he wants. I do not know of any cases where a child with problems grows up to live independently. Regression is relatively rare. It is being studied intensely by researchers now.
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Thanks for your reply. While waiting for the WES result, I read a lot about Phelan-McDermid. My son is 2 years old and he can’t show where his mum is, but he can point his finger to McDonald 🙂 As for the regressions, most people I’ve read had Shank3 mutations, not deletions. And almost always there was some factor that triggered it, such as vaccination, anesthesia, acute infection, drug poisoning, epileptic seizure, severe stress and vomiting in my son. He does not understand, if the gene does not work properly from the beginning, why does a well-functioning child lose acquired skills? Does a gene destroy something over time? Is it a neuroregressive disease? There are very few diagnosed children in Poland, only those who have a very severe course of the disease. The rest are diagnosed as autism. My son is also diagnosed with autism. Nowhere was the reason stated. And there must be some. Such as maternal age or infections during pregnancy.
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I can address a few of your questions. First, regressions have been seen most often in people with SHANK3 variants and with small deletions. However, researchers have also seen regression in some people with larger deletions. This is an area of intense study at the moment and we will know more as studies move forward.
There are two explanations regarding why a defect since birth leads to a problem later in life. This paradox has two explanations. First, the human brain is not done developing until at least the age of 22 years or so. An error introduced early in life, or even before birth, can lead to problems much later because the error impacts a developmental process that has not taken place yet. This can happen when building anything. The baby is not a finished product and even a teenager has not finished development. Things that work for a baby may not work for an adult because different circuitry is used by the adult.
The second explanation is specific to SHANK3. The Shank3 protein is used both for development and as the brain matures. Shank3 is used in the largest percentage of neurons of the brain. One process that many neurons do is called synaptic scaling. After learning something new certain synapses get larger. Then, presumably during sleep, the neuron re-adjusts all of its synapses. This is a balancing process so that no synapses get too large for the neuron to handle. The new synapses remain proportionally larger after learning, but the neuron regulates the overall size of all the synapses together. Most of the synapses are reduced in size to keep the proportions correct. Without this process (according to the theory), the neurons might have too many synapses that get too large and cost to much energy just to keep them all operating.
The problem is, when there is a problem with SHANK3, this synaptic scaling may get disrupted. Disrupted synaptic scaling may be one reason why learning is so difficult. It may also explain why a person with PMS can get stuck in an unwanted brain state. We all have moments of sadness or confusion or excitement. These are brain states that we go into, then out of. But, psychiatric problems can occur when someone get stuck in a brain state. I share with you these ideas about SHANK3 and brain states. In fact, these are just ideas that people discuss. There is no clear science yet that connects SHANK3 to synaptic scaling to brain states. However, the discussion is my way to explain how a brain can run into psychiatric problems when a gene is missing or has an unusual variant. These problems do not necessarily occur at a specific point in development. But, perhaps a person can get pushed into an unwanted brain state by severe stress, like anesthesia, acute infection, etc. A problem common to all psychiatry is how to get someone out of a brain state when they are stuck.
I hope you keep reading and thinking about how your son fits into the complex story of PMS. Some of your questions can be answered now in general terms. But, lots of the specifics are unknown. Over time, there will be more complete answers.
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