Originally posted 4 June 2015
Updated 1 April 2021
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.
Brain genes
The 22q13 region has at least 19 different genes that affect the brain and 10 reside in the terminal 1 Mb region. These genes sculpt the developing brain, protect it from damage, regulate excitability (e.g., avoid seizures), maintain healthy tissue and regulate cell death. In my next blog I discuss one gene that is a real mystery. This gene is found only in advanced primate species (e.g., humans, chimpanzees). Moreover, it has a unique, specialized role in the human brain. We still do not know enough about this gene, but we should not ignore it, either!
arm
Previous posts:
Can 22q13 deletion syndrome cause ulcerative colitis?
arm22q13 