CELSR1: Do some people with PMS have more fragile brains?

David has had many falls in his lifetime.

David enjoys walking, but his balance and coordination are not good. He has taken many falls in his lifetime. Sometimes he hits his head. He has had numerous stitches over his eye, on his forehead and has injured his nose more than once. I have always worried that these falls might have a cumulative effect on his brain.

In 2019, just before COVID-19 started to spread, a group of researchers in Shandong, China asked the question: what does the gene CELSR1 do? CELSR1 is on my list of high importance genes of PMS (see Which PMS genes are most important?) One copy of CELSR1 is missing in about half of all people with Phelan-McDermid syndrome who have a terminal deletion of chromosome 22. Only a few months ago I wrote about the relationship between CELSR1 and lymphedema (see Have we found the gene that causes Lymphedema?), based on research done elsewhere in China. As I describe in that blog, research on CELSR1 has become truly international.

It has been known for years that the CELSR1 gene is especially active (producing the celsr1 protein) following a brain injury. The celsr1 protein is associated with the creation of new neurons and enhancing the blood flow in the brain. Until now, it was not clear if the increase in celsr1 protein following injury protects the brain. Now we know a lot more. I will describe the research (see the scientific paper here).

The researchers used a very modern technique. They used a “short hairpin RNA” (shRNA) to reduce protein production by the CELSR1 gene in rodents. This method cut the level of the celsr1 protein production by 50%. Humans missing one copy of the CELSR1 gene should also have about a 50% loss in protein production. In other words, this is an animal model of PMS!

Using a standardized procedure to invoke a brain bleed in rats, the researchers looked to see if rats lacking half of the normal celsr1 sustained more brain damage than expected. Both the amount of brain damage and the ability to walk were significantly affected by the reduced celsr1. The researchers then refined their methods to analyze exactly how celsr1 was protecting the brain. Celsr1 is an amazing protein. It protects injured neurons from dying, it speeds up the production of new neurons and it promotes the formation of new blood vessels to provide oxygen to the injured region. The researchers were also able to pinpoint what part of the brain jumps into action when the celsr1 is needed.

For years, scientists have been looking for natural substances that might protect the brain after a bleed. These “neuroprotective” substances have been studied and they include familiar chemicals, like IGF-1. Thus far, none of the known chemicals or their derivatives have provided useful treatments for brain injury, intellectual disability or autism. The question becomes, is celsr1 nature’s way of protecting the brain? Perhaps we should be focused on restoring the normal level in people missing the CELSR1 gene?

We know that, in general, people with PMS who have larger than average deletions (average size is about 4.5 Mb) have more deficits/problems than people with smaller deletions. This has been shown repeatedly. What we do not know is whether people with deletions greater that 4.5 Mb accumulate brain damage over time. The brain bleeds (strokes) in the rat study are severe enough that a few of the animals die from the bleed. But, are smaller events — perhaps events that David experienced — causing serious long term problems because of the missing CELSR1? If these problems accumulate, perhaps the deletion size will be more important in older people with PMS.

This new information about CELSR1 reminds us that with each important gene comes an opportunity to help people with PMS. Some of the important genes remain poorly characterized. As we are seeing with CELSR1, the more we study these less-well-known genes, the more opportunities we have to develop new treatments.

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New science: SULT4A1, oxidative stress and mitochondria disorder

A visit with David during the COVID-19 epidemic

It has been known for some time that many people with Phelan McDermid syndrome (PMS) have mitochondrial issues. I discussed this in an earlier post (see Is 22q13 deletion syndrome a mitochondrial disorder?). At the time of that posting there were 17 PMS genes known to impact mitochondria. There is evidence that the PMS gene RABL2B generates a protein to transport mitochondria into synapses. That would be 18 genes. Now, new evidence has emerged that the SULT4A1 gene, a highly important PMS gene (see Which PMS genes are most important?) is critical for protecting the brain from oxidative stress by regulating mitochondria function.

After 20 years the role of SULT4A1 is finally coming to light. SULT enzymes have been known as important enzymes for a while, but SULT4A1 has always been a mystery. The other SULT enzymes have an active region used to regulate critical proteins in the cell, some involved with mitochondria function and the key neurotransmitter, dopamine. But, the SULT4A1 protein lacks the same active enzyme site. The other mystery has been that the SULT4A1 gene is highly specific for brain and brain development. Cathrine Ziats’ scientific paper last year found SULT4A1 to be one of the top 4 PMS genes expressed in the human brain during development (see her paper: Functional genomics analysis of Phelan-McDermid syndrome).

The new evidence paints a picture placing SULT4A1 as a critical regulator of brain metabolism. The thing to understand about the brain is that it sucks up 30% of the total body’s energy supply! This puts a huge load on the mitochondria of the brain. SULT4A1 regulates two other SULT proteins, SULT1A1 and SULT1A3. These enzymes are found on the outside membrane of mitochondria, connected together in pairs. By regulating these enzymes, SULT4A1 is able to crank up the output of the brain’s mitochondria. This reduces the reactive oxygen species, reduces oxidative stress and prevents neuronal damage. (See the two articles on PubMed: Hossain et al 2019 and Idris et al 2020). As SULT4A1 regulates these two other enzymes it can also regulate the effects of dopamine. Dopamine is a key neurotransmitter involved in learning and decision making. Too much dopamine, especially during development, can damage a cell. Too little dopamine is associated with motor and psychiatric disorders, like Parkinson’s disease and major depressive disorder.

Nearly a third of our PMS kids are missing the SULT4A1 gene (deletions larger than 7 Mb). Finding a way to fix the SULT4A1 gene would be a game-changer for these children. Like the other essential brain genes of PMS (e.g., SHANK3), the precise regulation of SULT4A1 is critical to normal development and healthy brain function. There are people with interstitial deletions of 22q13 that impact SULT4A1 without affecting SHANK3, and these people have severe developmental problems indistinguishable from others with PMS. (That some scientists are still arguing over whether or not to keep them in the family of PMS is a travesty, in my opinion as a father. See PMS, IQ and why interstitial deletions matter.)

We need more research on SULT4A1. We need treatments sooner rather than later.

 

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PMS, IQ and why interstitial deletions matter

David is nonverbal and music is very important to him

Originally posted 24 November 2018
Updated 27 November 2021
Available in Portuguese  https://pmsbrasil.org.br/pms-qi-e-por-que-as-delecoes-intersticiais-sao-importantes/

Phelan McDermid syndrome (PMS) is an intellectual disability developmental disorder. The most common reported form is a “terminal deletion” of the q end of chromosome 22. A terminal deletion occurs when a continuous segment of the chromosome is broken off at the end. Terminal deletions lead to intellectual disability (ID), language problems and coordination problems. Most people with PMS have additional problems (sleep disorder, feeding disorder, seizures, etc.), and these problems can often be severe. Many, perhaps most, have autism spectrum characteristics. I would argue that the hallmark trait of PMS is intellectual disability, because that manifestation of the disorder is the only one that occurs in 100% of people with a terminal deletion. By consensus, cases of unusual variants of the gene SHANK3 are also called PMS. These pathological variants of SHANK3 can have many of the same manifestations as seen with terminal deletions, although not all.

There are two related conditions that have lead to disagreement regarding what is and is not PMS. First, are deletions of 22q13.3 that do not disrupt SHANK3 (often called “interstitial deletions”) still called PMS? Second, does a person with a SHANK3 disruption, but without the hallmark manifestation (ID), have PMS?  Out of consistency, I would argue that a 22q13.3 deletions that causes ID should be called PMS, and SHANK3 variants that do not cause ID should not be called PMS. To go one step further, given two people with the same SHANK3 variant, one person might have ID (and therefor, PMS) and another person might not have ID. This unusual combination of circumstances has been observed. Likewise, two people with the same 22q13.3 interstitial deletion might or might not have PMS. This sort of definition is common with neurodevelopmental genetic syndromes. The genetics (called “genotype”) must cause a matching set of manifestations (called “phenotype”), to meet criteria for a named disorder. Some disorders have subtypes, but PMS has no official subtypes yet.

The rest of this discussion does not depend whether you call interstitial deletions PMS, treat interstitial deletions as a future subtype of PMS, or just avoid giving them a name. Understanding interstitial deletions is crucial to understanding PMS, because PMS can include the deletion of up to 108 different genes. Some of these genes are very important. If we want to end the suffering of PMS, we need to know which genes are important and in what way. Interstitial deletions can help teach us. Let me explain how, starting with old radios.

When I was a child I took apart radios to understand how they worked. This was a dangerous undertaking for a young boy. Radios were high voltage affairs in the old days. If the power mains didn’t kill you, burned fingers from hot vacuum tubes or a hot soldering iron left painful reminders of what not to touch. My logic in those days was to remove parts until the radio stopped working. The obviously necessary part was then soldered back into place and the hunt for more nonessential parts continued. When done, I still had a working radio, plus a collection of spare parts. “Working” did not always mean “working perfectly”.

Fifty years later, teams of scientists have used this same logic to grade the importance of each gene in the human genome. One such measure is the pLI score. Think of all people who are healthy enough to have children. Analyze every gene in every one of these people. Make a note of which genes in these healthy people are missing or incomplete in some way. These are the nonessential parts. A gene that is almost never missing or incomplete gets a pLI score of 1. It must be important. A gene that is often missing or incomplete gets a pLI score of zero. You can sound technical by calling the score a measure of reproductive fitness, but the theory is no more complicated than a 10-year-old with a soldering iron. Essential parts are almost never missing from people or radios. The pLI score is the measure of gene importance.

In 2018, a team of scientists studied all deletions greater than 50 Kb in groups of people with ID (Huguet et al 2018). Basically, they asked the question, “Can ID be explained by looking at the deletion size or (similarly) counting the number of genes deleted?” They came up with a formula: add up the pLI scores of all the deleted genes, multiple by about 2.6, then add the impact of known ID genes. That gives you the number of IQ points lost due to the deletion. (Technical note: I have averaged performance IQ and verbal IQ together).

Everyone has heard of IQ to measure intellectual ability. The IQ measure was designed so the median score on an IQ test is 100 across a large population. The work of Huguet et al, including subsequent work shows that you can predict the IQ loss caused by a deletion. A deletion removing genes with a cumulative pLI of 10 will reduce a persons IQ score by about 26 IQ points. The expected IQ of a person with such a deletion would be 100-26=74. This is not a good way to predict a child’s future IQ, since we don’t know if the child’s IQ would have been 75 or 125 without a deletion. But, if the prediction is a loss of 26 IQ points and the person has mild ID, it is likely that the genetic result essentially explains that person’s intellectual disability. There is an on-line tool to help do the calculation.

The next part is a little complicated, but PMS deletions are complicated. I hope everyone can understand at least the main points.

When we apply this IQ calculation to PMS, lots of strange things about PMS start to make sense. I will use a graph to explain. The graph below shows the number of IQ points that are lost when each part of chromosome 22 is deleted. It is a prediction based on some reasonable assumptions (which will not be discussed here). Read the graph from upper left to bottom right. The graph tracks how much the IQ falls as deletion sizes get larger and larger. I have an explanation below for each numbered circle on the graph.

Circle 1: Loss of SHANK3 at the very end of the chromosome (top left corner) has a major impact on intellectual function (IQ). See how the curve drops from 0 to -30 IQ points next to circle 1? I have assumed a SHANK3 deletion costs 30 IQ points, which is a big drop even for an identified intellectual disability gene.

Circle 2: Deletion of the next 1 Mb of the chromosome has a cost of another 20 IQ points. Already, we see that deletion of SHANK3 is not necessary to reduce ID. We also see that even relatively small 22q13.3 deletions (e.g. 1 Mb) can have a large impact over-and-above the loss SHANK3.

Circle 3: See how flat the curve is at circle 3? Additional deletion of the chromosome between 1.1 Mb and 4.1 Mb has virtually no impact. For those people who say that deletion size does not matter, that is why there are so many examples. The curve is flat and, indeed, in that region increased deletion size does not influence IQ.

Circle 4: IQ takes nearly a steady drop with deletion size in region 4. Nearly, because there are two “hot spots” with individual genes that appear to have a substantial impact. The proposed genes are CELSR1 and SULT4A1. I have written about these genes multiple times, see Which PMS genes are most associated with Autism?, What do we know about PMS genes? and CELSR1: Do some people with PMS have more fragile brains? Deletions in this region can cause serious intellectual disability. It is a clear example of how an interstitial deletion can cause ID, the primary manifestation of PMS.

Circle 5: An important intellectual disability gene shows up about 8.4 Mb from the end of the chromosome. This causes another steep drop in the curve comparable to (perhaps larger than) SHANK3. See my earlier blog about this gene (TCF20).

Circle 6: I have created a hypothetical example of a 2 Mb interstitial deletion. A 2 Mb deletion is about half the size of an average 22q13.3 deletion. This deletion causes a drop in IQ (27 IQ points) that is roughly equivalent to a SHANK3 deletion. Thus, from an intellectual disability perspective, interstitial deletions can easily be equivalent to other, more common cases of PMS.

This method of studying IQ impact of chromosome deletions was not created specifically for PMS, but it seems to apply very nicely. To accurately apply this method, we need to accurately measure the IQ cost of a complete SHANK3 deletion without including the effects of other genes. Calibrating the IQ cost of deletions, including SHANK3 loss, can be done by carefully studying cases of interstitial deletions. Current data from the longitudinal PMS studies may be sufficient if more effort is put into the analysis of interstitial deletions. Finally, the method can be used to identify who might need further testing. If the estimated IQ loss does not agree with the deletion size, the person could have other genetic issues worth exploring: a mismatch could be used to justify more detailed testing (e.g., whole exome sequencing).

The research in IQ loss associated with chromosome deletion shows that, for most people with 22q13.3 deletion syndrome, fixing SHANK3 is likely to be beneficial, but not a cure. SHANK3 accounts for less than half the intellectual disability for an average size deletion (4.5 Mb) and less than 25% of a large deletion. Finally, we need to take interstitial deletions more seriously. From a scientific perspective they are hugely informative. From a PMS perspective, they are part of the same disorder.

Interstitial deletions matter because 1) they can be used to help calibrate IQ loss as a function of deletion size, 2) they can help identify which genes cause some of the manifestations of PMS not caused by SHANK3, and 3) effective treatments of PMS will depend upon how well we can treat all the important genes of 22q13.3.

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Some previous blogs

MAPK8IP2 (IB2) may explain the major problems with walking and hand use
TCF20 may explain why some big deletions are worse than others
Current trends in SHANK3 research
Which PMS genes are most associated with Autism?
Does SHANK3 cause Autism?
We need to study interstitial deletions to cure PMS
What do we know about PMS genes?
Which PMS genes are most important?
Are children with Phelan McDermid syndrome insensitive to pain?
Looking for Opportunities
Splitting, Lumping and Clustering
Defining Phelan McDermid syndrome
Why don’t we have better drugs for 22q13 deletion syndrome?
What do parents want to know?
Have you ever met a child like mine?
How do I know which genes are missing?
Mouse models
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
22q13 deletion syndrome – an introduction

TCF20 may explain why some big deletions are worse than others

David is quite the fan of Jimi Hendrix

I don’t know how big David’s deletion is, but he has all the hallmarks of a PMS individual with a large deletion. His developmental delays were substantial: walking took 6 years and full oral feeding required 3 more years. He is nonverbal and even as an adult it is difficult to estimate his receptive language.

Deletion size explains some of the differences between individuals, but any given individual may be far from the “average” for a given deletion size. Is deletion size unimportant? TCF20 is a PMS gene that can help explain some of the mystery.

I have started cataloging all the different factors that influence phenotype (the features of people with a disorder). The number of factors and how the different factors interplay is rather staggering. It has been known for over a 100 years that even a relatively small number of genetic factors can produce a rather wide spectrum of phenotype characteristics. “Phenotype variability” is the term used to describe the diversity. As I progress on the cataloging of what causes phenotype variability in PMS, I will blog on various aspects and examples.

This blog is on TCF20, an important PMS gene that is lost in large (over 8.6 Mb) terminal deletions and some interstitial deletions. I mentioned that TCF20 is an important brain development gene in an earlier blog (What do we know about PMS genes?). TCF20 has all the characteristics of an important gene based on several different studies. At the time I wrote that blog I did not notice a paper (Prevalence and architecture of de novo mutations in developmental disorders) in Nature, a top scientific journal. In that study, the authors were able to affirm TCF20‘s role in genetic disorders. The cases they studied were not PMS, with large deletions. These cases were de novo mutations. Their results show that loss of TCF20 function can, on its own, cause a developmental disorder. It is yet another reminder that a number of PMS genes can cause disorders on their own, without any involvement of SHANK3.

This blog is about phenotype variability. TCF20 provides not one, but two examples of variability. These two factors operate together to explain why some kids with large deletions are more impacted by deletion size than other PMS kids.

Large deletions that are almost the same size can be very different from each other. An 8.5 Mb deletion does not impact TCF20, whereas a 8.6 Mb does. We can be confused about the impact of deletion size if we do not look closely at the genes. That is the first factor: a small change in deletion size can have a large effect. Note that the opposite can also be true. In some locations on chromosome 22, large changes (500 kb or more) can be unimportant.

The second factor is a bit more subtle. A recent paper has affirmed something else about TCF20.  TCF20 is especially sensitive to “genomic imprinting” (Genome-wide survey of parent-of-origin effects on DNA methylation identifies candidate imprinted loci in humans). Normally, either copy of a gene is used by the cell. Genomic imprinting is when only one copy of a gene is used by the cell. The other copy is permanently turned off, never used. Consider this, if someone has a large deletion, but the deletion removed the copy of TCF20 already turned off, the deletion will have no effect on the production of TCF20 protein (a transcription factor). On the other hand, if the large deletion removed the active copy of TCF20, no TCF20 protein will be produced by the cell. Thus, for TCF20, “genomic imprinting” can determine whether deletions over 8.6 Mb are more devastating than smaller deletions. The two factors, deletion size and genomic imprinting, operate together. We cannot predict the effect of one without understanding the other.

Very few PMS genes are subject to genetic imprinting, but this story serves as an example. We have the scientific tools to explain phenotype variability. There are cases where deletion size seems unimportant, but these cases can be explained. The many factors that influence the future of a baby with PMS are not magical. Many people have overestimated the role of SHANK3 because PMS phenotype variably seems so mysterious. Genetics are complicated, but not mysterious. TCF20 provides a great example of how applying the science carefully can uncloak some of the mystery.

 

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Previous blogs

Current trends in SHANK3 research
Which PMS genes are most associated with Autism?
Does SHANK3 cause Autism?
We need to study interstitial deletions to cure PMS
What do we know about PMS genes?
Which PMS genes are most important?
Are children with Phelan McDermid syndrome insensitive to pain?
Looking for Opportunities
Splitting, Lumping and Clustering
Defining Phelan McDermid syndrome
Why don’t we have better drugs for 22q13 deletion syndrome?
What do parents want to know?
Is 22q13 deletion syndrome a mitochondrial disorder?
Educating children with 22q13 deletion syndrome
How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?
Mouse modelsScience Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

Educating children with 22q13 deletion syndrome

David is tolerant of my picture taking

If you ask me what is wrong with David, I don’t think I can answer the question without making a laundry list of problems, deficits and other issues. He has 22q13 deletion syndrome – that is what’s wrong.  Some of his problems almost killed him.  Someday, that risk may return.  In the meanwhile, his biggest problem is learning new knowledge and skills.  Can we make learning more efficient for our children?  To investigate this question, we need to understand more about how individual and groups of genes can affect the brain.

I have written blog posts on specific issues (cancer, ulcerative colitis, hypotonia) and other issues in the context of individual genes. Individual genes can impact many parts of the body.  A single gene may have multiple functions, an effect called “pleiotropy” (plahy-o-truh-pee).  We are often concerned with the primary impact of a gene more so than the secondary issues.  For example, CTFR is a cystic fibrosis gene. Its impact on the lungs is very damaging, but it also impacts other parts of the body.

Many 22q13 deletion syndrome genes are pleiotropic.  We must look carefully at all the potential effects of a gene.  Why? Because, so many genes are lost in 22q13 deletion syndrome that subtle effects can add up. When I read the scientific papers on a gene, I spend a lot of time comparing the subtle effects of this gene with all the others.  I look for cases where multiple genes have subtle effects on the same organ. By definition, 22q13 deletion syndrome is a chromosomal deletion syndrome.  It is not a monogenic syndrome as some have suggested.  I recommend using the name “Phelan-McDermid syndrome” if you want to combine SHANK3 mutation syndrome with 22q13 deletion syndrome. See: Introduction to 22q13 deletion syndrome and How to fix SHANK3.

Pleiotropic effects come in two flavors.  Either the gene has one function, but in different parts of the body, or the gene can do more than one function.  CTFR, is not a 22q13 deletion syndrome gene, but it provides a useful example.  It is the most common cystic fibrosis gene.  CTFR is involved in making secretions (fluids used in the body). CTFR mutations are most important in the lungs, but the gene also causes faulty secretions in the digestive tract, and elsewhere.

CELSR1 is a 22q13 deletion syndrome gene.  Over 40% of our children are missing this gene.  Like CTFR, one function affects many different parts of the body.  If one copy of CELSR1 is mutated, the most serious result is a neural tube closure defect (e.g., spina bifida or other spinal cord problems).  Mouse studies of Celsr1 show that it participates in helping cells organize into physical patterns so that cells can operate as a group. Celsr1 is involved in early development by organizing certain cells into functioning tissues (Feng et al, 2012).  However, the central role of CELSR1 in adult brain function was only discovered last year (Schafer et al, 2015).

During development, Celsr1 mutations can interfere with the organization of many different cells (Boutin et al, 2014). For example, ventricles are nourishing fluid lakes inside the brain. Cilia, cells with tiny hairs, line the ventricles of the brain and stir the cerebrospinal fluid (CSF) along its path through the ventricles. Stagnation of the CSF fluid is dangerous. Disordered cilia from Celsr1 mutations cause inefficient motion. In humans, stagnant CSF may have accumulating impact over years.

Very different cells with cilia are used in the ear to hear sounds. CELSR1 mutations disrupt the orientation of “outer hair cells,” responsible for hearing at low sound levels. Cilia are responsible for other body functions, as well, like keeping the airways clear and digesting food. Given its impact on different organs, CELSR1 is pleiotropic.

When someone asks me what is wrong with David, one of the first things I say is he struggles to learn.  David is aware and interested in his environment, but he knows trying to learn anything new is difficult.  My last blog discussed SHANK3 and its impact on learning that involves the ventral striatum in the brain.  Mutations in CELSR1 disrupt a different kind of learning, learning that is unique to the hippocampus of the brain.  Only two areas of the brain are able to grow new neurons.  One of these areas feeds the new neurons into the dentate gyrus of the hippocampus and has a subtle, but critical effect on learning . Mutation of rodent Celsr1 disrupts the orientation of these new neurons in the hippocampus.  This disruption interferes with building proper connections (Schafer et al, 2015).  Thus, children with deletions greater than 6 Mbase are likely have problems with “pattern separation,” the very subtle learning process that prevents new learning from interfering with old knowledge (Johnston et al, 2015).  The concept of pattern separation has arisen through complex mathematical learning models.

How can we take this information on CELSR1 and translate it into treatments?  There are several paths.  First, we would like someone to study a mouse missing one complete copy of Celsr1 (heterozygous knockout mouse) to make sure the effects seen in the current mice are not simply mutation effects (see Gene deletion versus mutation).  There is a scientist in Belgium, Fadel Tissir, who has a “null” mouse (no copies of the gene), but has not reported any studies with a heterozygous knockout mouse yet.  Second, we need to find out about outer hair cell loss and its potential impact on hearing.  Perhaps someday we can arrange for a medical histologist to examine the cochlea (hearing organ) from a 22q13 deletion syndrome organ donor. Third, we need genetic testing (sequencing is best) on all patients missing CELSR1 to identify cases where the remaining CELSR1 gene is mutated.  A mutation on the remaining CELSR1 gene could unmask recessive traits in a way that may be very informative.

Finally, if we really want to understand our children’s learning problems, we need to: 1) engage people involved in computational models of learning, and 2) study patients with interstitial deletions.  Interstitial deletions will allow us to study genes in better isolation.  These patients may be higher functioning, which is ideal for careful testing (see How to fix SHANK3). As the new studies start to bear fruit, we can then use the results to target our teaching methods.  Right now parents, teachers and our children are frustrated with how poorly our children learn. Imagine how much better it will be when we know how to maximize learning for each child based on their genetic report.  I dream of seeing the next generation of children with 22q13 deletion syndrome having all the benefits we never had for David.  Let’s take lesson planning into the 21st century!

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Previous blogs

How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?
Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

Have you ever met a child like mine?

Sometimes, David likes to be held.

Jannine Cody, the parent/scientist who studies 18q deletions, says that since every deletion is different, every child with a deletion is different.  At the PMS family conferences we met other children with 22q13 deletion syndrome who, at the time, had striking similarities with David.  These children had chromosome 22 deletions of various sizes, and similar children did not always seem to have the same size deletions.  We know now that genes are not distributed equally along 22q13, so children with small deletions can be quite different from each other, and children with large deletions can be quite similar (see Understanding deletion size).  We also know there are good scientific reasons to expect differences (see How can the same deletion have such different consequences?).  Some things are pretty obvious after a while.  The kids who could not walk or talk generally had larger deletions.  Those with larger deletions also had many more medical problems.  Obviously, more genes lost means more problems.  Regular readers of this blog have seen evidence of why it is very important to know which genes are missing (see How do I know which genes are missing?).

Some people feel that research on 22q13 genes should be done one gene at a time, starting with SHANK3.  I am not a big proponent of this approach, since it ignores a lot of research already done on ARSA, MAPK8IP2, CHKB, CPT1B,  PANX2, ALG12, BRD1, SULT4A1 and other genes known to cause disorders in humans, mice or both.  The one gene-at-a-time approach also slows research by making one gene sound much more important than others.  It seems to me if we spend 5 to 10 years on each gene, we are doomed to spending 500 to 1,000 years. If that sounds pretty absurd, well, it is.  Maybe it will only take 200 years to do it this way.  That still seems too long to me.  That is why I recommend the scientific program be managed by someone with a deep understanding of science leadership (see 22q13 deletion syndrome and science leadership).  The “SHANK3 or bust” research program has succeed in some ways.  Recently, after about a dozen mouse models of Shank3, there is a new mouse with the first complete deletion of the gene. All the other mice were various examples of gene mutation.  As we know, the effects of mutation (or removing part of the gene) can be very different from deletion (see Gene deletion versus mutation: sometimes missing a gene is better). This is critically important! The main reason for supporting Shank3 mouse research is the argument that most (not all) patients are missing the SHANK3 gene entirely.  Thus, it is SHANK3 deletions that make the research important to our families. (Note that mouse Shank3 mutation research has a very separate goal: understanding how mutations might contribute to general forms of autism.)

So, we now have a real Shank3 deletion mouse and everyone is very excited about it (Mouse Model of Autism Offers Insights to Human Patients, Potential Drug Targets).  Of course, be skeptical of what the university PR team says (see Mouse models).  Let’s take a look at this first-ever complete Shank3 knockout mouse. First off, the major finding is that this mouse is different from the many mutation mouse models.  No one should be surprised.  What is surprising is that you have to completely wipe out 100% of Shank3 to see a measurable difference between these mice and normal mice. Even more shocking is that these mice are walking around, playing with other mice, eating, talking mice talk (ultrasonic sounds) with no shank3 whatsoever in their bodies!  The mice missing 100% of Shank3 are different from other mice, but mice missing 50% are not different in any measurable way. Note that humans with 22q13 deletion syndrome are missing only one of the two genes and best evidence is that they have lost only about 25% of their shank3 protein (See this research paper).

So, is there something wrong with the mouse study?  Are mice just way different from humans, or is there another explanation?  Maybe it all makes sense.  Have you ever met a human missing all of SHANK3 and only SHANK3?  The complete knockout Shank3 mouse is best compared with a person like that, someone who is not missing any other genes and has no known mutations.  It is not good enough to have someone with a “small deletion”, since there is strong evidence that adjacent genes impact brain function.  This mouse models SHANK3 deletion.  I have met only one person who seems to fit this description.

Phelan McDermid syndrome is characterized by developmental delays, moderate to severe intellectual disability, little or no expressive language, and infant hypotonia (floppy baby syndrome).  Some people argue that the syndrome is also characterized by a high incidence of autism spectrum disorder, although some top scientists disagree.  The person I met was probably never a floppy baby, has practically normal speech, and that person has no evidence of autism.  Rather, the person I met has some problems with coordination, has a great difficulty learning and is socially a wonderful person to meet and engage with, perhaps to a fault.  Tragically, like all of our children, that person will never navigate the world well enough to live an independent life.

In summary, when I read the scientific paper on the complete Shank3 knockout mouse, what struck me was how many tests the complete, 100% knockout mouse passed without demonstrable evidence of a problem. Mice missing one copy are normal in almost every test.  Mice missing both copies are not “normal”,  but clearly, even these mice are nothing like my son.

How important is SHANK3?  It is impossible to make that judgement based on only one clinical case.  The person I met has lost all independence for that person’s entire life. That is very important.  Moreover, it is tragic.  But for 95% of families, 22q13 deletion syndrome comes with the full set of core features of 22q13 deletion syndrome.  David cannot tell me when he feels sick, where it hurts, or if he was mistreated in his group home. It took him 6 years to overcome his floppy baby syndrome enough to walk and three more years before he could eat by mouth.  His autism-like features interfere with social contact.

As of now, the most parsimonious explanation of what we know is that SHANK3, alone, does not produce the core features of 22q13 deletion syndrome.  It is a contributor in most, but not all, cases.

 

arm22q13

 

Previous blogs

How do I know which genes are missing?
Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

 

How do I know which genes are missing?

David decided to stand still so I could
take his picture.  Thanks David!

Originally posted 5 March 2016
Gene list corrections 6 March, 12 March, 17 June, 5 Dec 2016
Gene list correction 7 April 2017
Text edited 7 April 2021
Available in Portuguese http://pmsbrasil.org.br/como-saber-quais-genes-estao-faltando/

I often get asked to interpret a genetic report. I am not a clinician of any sort. I never even had a genetics course in college. But, there are certain skills one must pick up along the way to study which genes are missing in 22q13 deletion syndrome (Phelan-McDermid syndrome, PMS) and what they do. So, I have some idea how to read a report. Recently, I worked with Dr. Teresa Kohlenberg to create a page for PMS parents called: How to read a genetic report: examples from Phelan-McDermid syndrome (PMS).

If you have a genetic report it may not list which genes are missing. Often genetic reports only list “OMIM genes”. This list is not complete and it can be misleading. A good genetics consular may sit down with you and try to explain everything, but frankly only a geneticist can take it all in at once. If your child has a 22q13 deletion there are some ways you can find out which genes are missing on your own. This approach does not work in every case. Sometimes the genetic test itself is not precise enough. David had a FISH test 15 years ago. It is definitive for diagnosing PMS, but it is not sufficient to figure out which genes he is missing. If your child has a SHANK3 variant and no other genetic result, then you do not need to go looking for a list of genes. Only one gene is involved. If that seems unclear, read my blog The four types of Phelan McDermid syndrome

These days most children tested have a CMA (“array”) test and the following information will be helpful. I will cover different methods here. Often, the most practical method is to use the list of genes (see below). 

What experts do (Expert mode)

The experts use the technical part of a genetic report to see what has been deleted. The technical part will often look something like this. This nomenclature is explained in detail at the page How to read a genetic report.
hg17  arr 22q13.33 (48,230,183-49,523,149) X1
This example is a simple terminal deletion of chromosome 22 (not a real case).  It says that part of chromosome 22 only has one copy (X1). The nomenclature can get complicated, especially if there are multiple genetic problems. 

Once the expert knows which base-pairs are missing (48,230,183-49,523,149 in this case) and which genome assembly was used to make the measurement (hg17 in this case), he/she/they can go to the UCSC Genome Browser and get gobs of information about the deletion. The Genome Browser is complicated to use, but I use it often. It is densely packed with genetics information gathered from many sources. It can quickly provide a complete list of genes that are lost by a chromosomal deletion. 

Simplest

Sometimes a genetic report will provide a complete list of the missing genes.  “Complete” is relative to certain things. For instance, most gene array studies cannot detect the presence or loss of the last gene on the chromosome, RABL2B. This gene is too similar (in its sequence) to RABL2A and lax thinking about RABL2B has interfered with careful interpretation of its putative role in brain function. (See my blog Is 22q13 deletion syndrome a ciliopathy.) Otherwise, the gene list is useful. If the only genes listed are SHANK3 and ARSA, the deletion is very small or the list itself is far from complete. I am not a big fan of genetic reports that omit lots of information, even if a parent is not ready to absorb the information right away.

End gene or deletion size

If the deletion is a terminal deletion (the most common type), you can use the deletion size to look up the missing genes with the aid of my list (below).  If the report says something like, “from PLXNB2 to ACR” or “distal to” PLXNB2, then you can find PLXNB2 on the list and the deletion includes all the numbered genes lower than PLXNB2 (number 20 on the list). 

Go to the Foundation’s web site?

If you had 18q deletion syndrome, there is a site that was created for parents to look up the genes that are missing and what those genes do. No such site exists for 22q13. My blog is your best resource. 

Ask your geneticist

I have seen some very nice genetics reports with a complete list of genes deleted.  This is not always the case, but you might try asking your geneticist to supply a complete list of genes deleted. 

The list

Here is a list of the genes that covers the last 9.3 megabases (Mb) of 22q13. That is about the size of the largest known 22q13 terminal deletion. The list comes with a few caveats. First, deletions can be messy. Sometimes lots of genes are gone, then part of the next gene is also gone. People do not count half a gene. I usually add the partial gene to the list of missing genes, since the gene has been damaged at that point. Chromosomal microarrays (a.k.a. CMAs, arrays or gene chips) sample the chromosome every so often (every so many bases). It is not a continuous readout of the chromosome. Thus, in most cases, you don’t know the exact position of the break, but you will be given a number that is very close.  The DNA of a chromosome includes many things in addition to genes. It encodes things called microRNAs, promotors, inhibitors and enhancers. There are regions called “open reading frames”. The gene list I provide does not include these less-well studied regions of the chromosome. My list is limited to protein coding genes. Suffice it to say that a gene list tells only part of the story, but it is an important part. That said, this list comes without any warranty whatsoever. I take no responsibility for its use. It is part of a blog to educate parents. It is not a tool for legal, medical or any other practice. Ok?

The gene are number from the end of the chromosome. The deletion size value is the distance from the end of the gene to the end of the chromosome. For example, if your child has a terminal deletion of size 1 Mb (same as size 1,000 kb), then your child is missing one copy of the genes numbered 1 through 36. If the deletion size is 4.5 Mb, then the genes numbered 1 through 44 are deleted. 

 

#       Gene       Deletion size (kb)
1       RABL2B        34.81 
2       ACR           78.11 
3       SHANK3        85.17 
4       ARSA         195.14 
5       MAPK8IP2     206.92 
6       CHKB         235.47 
7       CPT1B        240.05 
8       SYCE3        255.56 
9       KLHDC7B      267.45 
10      ODF3B        286.65 
11      TYMP         288.47 
12      SCO2         292.86 
13      NCAPH2       295.00 
14      LMF2         310.78 
15      MIOX         328.43 
16      ADM2         332.03 
17      SBF1         343.44 
18      PPP6R2       373.38 
19      DENND6B      491.41 
20      PLXNB2       539.63 
21      MAPK11       548.08 
22      MAPK12       557.16 
23      HDAC10       567.21 
24      TUBGCP6      573.90 
25      SELO         600.85 
26      TRABD        618.90 
27      PANX2        638.18 
28      MOV10L1      656.85 
29      MLC1         733.11 
30      TTLL8        763.84 
31      IL17REL      809.78 
32      PIM3         854.39 
33      CRELD2       895.76 
34      ALG12        900.01 
35      ZBED4        928.39 
36      BRD1         995.26 
37      C22orf34     1,160.96 
38      FAM19A5      2,067.65 
39      TBC1D22A     3,642.77 
40      CERK         4,080.21 
41      GRAMD4       4,180.53 
42      CELSR1       4,281.30 
43      TRMU         4,484.77 
44      GTSE1        4,487.66 
45      TTC38        4,543.18 
46      PKDREJ       4,555.11 
47      CDPF1        4,570.18 
48      PPARA        4,620.06 
49      PRR34        4,764.32 
50      WNT7B        4,841.34 
51      ATXN10       4,973.16 
52      FBLN1        5,287.14 
53      RIBC2        5,385.97 
54      SMC1B        5,404.90 
55      FAM118A      5,508.30 
56      UPK3A        5,522.59 
57      KIAA0930     5,577.70 
58      NUP50        5,630.45 
59      PHF21B       5,809.48 
60      ARHGAP8      5,955.68 
61      PRR5         6,080.79 
62      LDOC1L       6,320.17 
63      KIAA1644     6,505.62
64      PARVG        6,610.00 
65      PARVB        6,649.55 
66      SAMM50       6,821.94 
67      PNPLA3       6,870.90 
68      PNPLA5       6,926.46 
69      SULT4A1      6,955.97 
70      EFCAB6       7,248.33 
71      MPPED1       7,310.62 
72      SCUBE1       7,475.08 
73      TTLL12       7,631.34 
74      TSPO         7,655.23 
75      MCAT         7,675.07 
76      BIK          7,688.76 
77      TTLL1        7,729.13 
78      PACSIN2      7,942.26 
79      ARFGAP3      7,961.07 
80      A4GALT       8,123.48 
81      ATP5L2       8,177.87 
82      CYB5R3       8,173.96 
83      RNU12        8,203.08 
84      POLDIP3      8,203.60 
85      SERHL2       8,260.06 
86      RRP7A        8,298.67 
87      SERHL        8,305.91 
88      NFAM1        8,386.07 
89      TCF20        8,603.03 
90      CYP2D6       8,688.56 
91      NDUFA6       8,727.69 
92      SMDT1        8,735.12 
93      FAM109B      8,739.03 
94      NAGA         8,747.64 
95      WBP2NL       8,785.70 
96      SEPT3        8,828.88 
97      CENPM        8,871.30 
98      TNFRSF13C    8,891.65 
99      SHISA8       8,903.80 
100     SREBF2       8,911.16 
101     CCDC134      8,992.58 
102     MEI1         9,019.01 
103     C22orf46     9,124.62 
104     NHP2L1(SNU13)9,129.56 
105     XRCC6        9,154.43 
106     DESI1        9,197.37 
107     PMM1         9,228.58 
108     CSDC2        9,241.80 
109     POLR3H       9,273.98 
110     ACO2         9,289.48 

That’s it. If you know the deletion size you can figure out which genes are missing. There are some cases of PMS where the deletion does not continue to the end of the chromosome (often called “interstitial deletions”). The list is still relevant, but identifying the genes in that (and other complex cases) requires a few more steps. For most families, using the list should be straightforward given a deletion size.

I want to thank the parents who have shared genetic reports and shared their own very personal stories. Your contributions and feedback help me feel that I am not alone in the quest to make the world a better place for our children.

 

arm22q13

 

Some previous blogs

Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
22q13 deletion syndrome – an introduction

Comment la même suppression peut-elle avoir une telle variété de conséquences ?

[English version]

L’auteur, Andy, et sa cousine ont la même chromosome hybride 22 qui provoque le syndrome de la suppression 22q13.

Leurs enfants ont la même suppression mais un des enfants d’Andy est mort et l’autre, David, a failli mourir. La cousine n’a pas eu cette expérience et sa fille, contrairement à David, n’a pas pris 6 ans à apprendre à marcher, 9 ans à manger oralement et elle peut parler avec les phrases courtes. C’est la question la plus posée par les parents d’enfants atteints.

Si SHANK3 n’est pas la cause de la suppression 22q13, pourquoi y a-t-il un enfant avec uniquement la mutation SHANK3 qui ne sait ni parler ni marcher ? Et il y en a d’autres qui savent très bien marcher et parler. Si vous acceptez la dilemme que des suppressions similaires peuvent provoquer des résultats très différents, il n’y a plus l’argument du gène favori (SHANK3 aujourd’hui, demain autre chose probablement.)

Pour expliquer ces différences il y a plusieurs réponses :

1. Perte de l’hétérozygotie : Des petites erreurs génétiques ont lieu tout le temps pendant le développement et dans la vie adulte. Facteurs environnementaux – radiation, infections, coups de soleil, toxines. Le fait d’avoir les paires de gènes de deux parents différents nous protège des erreurs génétiques graves. Lorsqu’il manque des gènes à cause d’un syndrome de suppression, on n’a qu’une copie d’un gène alors il y a l’occasion parfaite pour des erreurs non-corrigées. Si ce gène est endommagé par la suite, les conséquences peuvent être graves. L’erreur peut être globale (corps entiers et détectable avec les tests génétiques) ou local (limité à une partie du corps ou du cerveau.) Quand l’erreur est locale elle n’est pas détectable et devient une différence inexpliquée.

2. Impression (ou empreinte ?) : Quand un des gènes est éteint comme le syndrome d’Angelman. Si la seule copie qui reste du gène s’éteint ça va provoquer des problèmes qui ne seront pas expliquées.

3. Impact de la mutation du gène : Souvent un gène qui est supprimé a moins d’impact qu’un gène qui a subi une mutation. Comme dans le cas des cellules de cancer ; on préfère qu’elles meurent au lieu de pousser avec des gènes modifiés. Si une suppression chromosomique ne frappe qu’une partie du gène, le gène peut commencer à créer des protéines qui empêchent le fonctionnement normal de la cellule et la petite suppression provoque des grands problèmes.

4. Les combinaisons de gènes : Quand il y a plusieurs suppressions et mutations on cumule les erreurs génétiques et chacune fait sa contribution. On a parfois des gènes qui, seuls, n’ont pas d’impact lors de leur suppression/mutation mais avec certains autres peuvent avoir des conséquences beaucoup plus importantes. On ne comprend pas encore ces combinaisons alors on utilise des termes comme ‘antécédents génétiques’ en attendant. La différence génétique principale entre David et la fille de la cousine d’Andy vient de la femme d’Andy et du mari de sa cousine ; des différences dans leurs antécédents génétiques.

5. Mosaïcisme et mutations somatiques : Pendant le développement les erreurs génétiques peuvent avoir lieu dans une petite partie du cerveau. Ces erreurs peuvent expliquer les variations comme les difficultés d’apprentissage. Ces mutations inaperçues peuvent avoir des incidences plus lourdes lorsqu’elles interagissent avec les 30 à 100 gènes manquants. L’impact de SHANK3 peut être amplifié par ces gènes modifiés ou perdus dans des parties spécifiques du cerveau.

6. Les régulateurs génétiques: Le projet génétique ENCODE tente de trouver tous les morceaux régulateurs des gènes de l’ADN. La plupart de l’ADN est composée de régulateurs de gènes. C’est plus facile à comprendre quand vous vous rendez compte que les cellules de foie, de peau, des intestins, du cerveau, ont toutes les mêmes gènes. Ce qui change est les gènes qui sont actifs ou inactifs. Les cellules de peau savent qu’elles sont cellules de peau et n’utilisent que les gènes de cellules de peau. L’ADN est réglé dans chaque tissu à associer la signature génétique nécessaire à fabriquer le tissu. Les suppressions chromosomiques 22 suppriment également les régulateurs de gènes. Les régulateurs sont très difficiles à repérer et pourraient être la cause de ces différences inexpliquées.

Compte tenu de la complexité et de nombreuses possibilités de variation inexpliquée , nous pouvons commencer à apprécier que la connaissance de la taille de suppression d’un individu ne fournit pas toutes les réponses. Cependant, grâce à des outils modernes, il existe des moyens pour étudier les effets de la taille de la suppression même avec une telle variabilité. Ces outils peuvent être utilisés pour démêler les gènes qui contribuent à chaque problème médical. Cela exige un engagement sérieux des parents à pousser les chercheurs et le personnel médical vers ces recherches, tirant pleinement parti des rapports génétiques. Trop l’accent sur un gène préféré entrave le progrès scientifique et médical. Ceux qui travaillent sur un autre chromosome, syndrome de délétion (suppression 18q syndrome) ont étudié leur syndrome à bon escient au cours des 50 dernières années. Ils se tournent vers la médecine scientifique pour les symptomes de 18q (Voir Création d’ anomalies chromosomiques). Les personnes 18q ont développé une feuille de route, que les gens atteints du syndrome de délétion 22q13 peuvent facilement suivre (Voir Conséquences du chromosome 18q suppression). J ai travaillé durement dans mes dernières recherches pour faire ce point , mais rien est plus convaincant que de voir d’autres prendre les devants avec une telle clarté et tel engagement. Pourquoi n en avons-nous pas profité ? La seule explication que je peux trouver est que la communauté du syndrome de délétion 22q13 manque de personnes qualifiées, dirigeant scientifique impartiale. Il y a un problème assez évident, avec des conséquences très tristes. Il n’y a pas plus de traitements pour David aujourd’hui qu’il ya 30 ans. Nous savons quels gènes sont portés disparus et pour beaucoup d’entre eux, nous savons ce qu’ils font (Voir Comment savons-nous quels sont les gènes 22q13 suppression: l’espoir de la médecine de précision). Ce que nous ne semblons pas savoir est comment rendre le travail de la science meilleur pour le bien de nos familles.

 

[My thanks to Betty Sepré for doing this translation.  That said, I take responsibility for any errors in typing, translation or content. Feel free to contact me with corrections. –  arm22q13]

How can the same deletion have such different consequences?

David at 3 days of age: David’s deletion size is exactly the same as his cousin’s, yet the deletion had more severe consequences.

Originally posted 19 January 2016
Updated 19 July 2021
Available in Portuguese  http://pmsbrasil.org.br/como-a-mesma-delecao-pode-ter-consequencias-tao-diferentes/

Introduction

There is a common question among parents of children with 22q13 deletion syndrome. Why is one child with a larger deletion able to talk, while another child with a much smaller deletion nonverbal? Unexplained differences in “phenotype ” (the manifestations of the disorder) can be confusing to parents. Some parents conclude that deletion size is unimportant, but that is incorrect. A sports a team can have good days and bad days. The team is judged on its overall record. Genetics are similar. A deletion in one individual can be more or less impactful, but it is the overall statistics of deletions that demonstrates the clear effect of deletion size.

The person-to-person variation is especially striking when we look at how the same genetic arrangement can have very different outcomes. My cousin and I inherited the same abnormal chromosome. Somewhere back in family history, tiny bits of chromosomes 19 and 22 got swapped (see Who is arm22q13?). My genetics include a hybrid and unhelpful chromosome 22 that has caused 22q13 deletion syndrome in my children (see Understanding translocations in 22q13 deletion syndrome: genetics and evolution). My equally unfortunate cousin had the same chromosome inherited from our grandfather. Despite inheriting the exact same deletion, our children turned out very differently. Both of my kids who received this chromosome were failure-to-thrive babies. One died a few days after birth and the other one almost died (see photo of David, who lived). My cousin had no such experience. Her daughter has 22q13 deletion syndrome, but without perinatal problems. Her daughter’s case of PMS is not as severe as David’s. For example, David does not talk at all but his cousin talks in short sentences. Why has virtually the exact same deletion had such different consequences? The effect is called phenotype variability.

Phenotype variability even occurs within the SHANK3 gene. Two people with the same pathogenic variant can differ vastly in their ability to walk or talk. Once we accept the dilemma that similar deletions can have very different outcomes, we are in the right frame of mind to try understanding this phenomenon.

Explaining variation

So, how do we explain these dramatic differences? The answer is: there are many answers. There are so many ways similar deletions can have very different outcomes, that it takes a catalog of explanations to cover them. Here we go.

1. Loss of heterozygosity (a.k.a., hemizygosity). Small genetic errors occur all the time during development and in adulthood. Environmental factors from cosmic radiation to infections, sunburn to environmental toxins, can create small errors. Cells have mechanisms to repair errors, but one important hedge against serious genetic errors is the fact that we carry two of every gene (one from mom and one from dad). When a person or a tissue in the body has only one copy of a gene, there is an unfortunate opportunity for errors to go uncorrected. 22q13 deletion syndrome is the loss of some or many genes on one chromosome. This creates hemizygosity (“half as many copies”) of those genes. Any uncorrected error in the sole remaining gene can have a dramatic effect. Loss of one gene, then damage to the remaining gene is sometimes called a “2nd hit”. The error can be global (whole body and detectable with genetic testing), or it can be local (limited to one small region of the body, or one region of the brain). When it is local, it is undetectable and becomes an unexplained difference.
2. Imprinting. Imprinting is when one of the two inherited genes is silenced (turned off). Angelman syndrome is an intellectual disability syndrome with a number of similarities to 22q13 deletion syndrome. It is caused by imprinting that turns off an important gene. Not much is known about how imprinting and chromosomal deletions interact, but obviously it would be a problem if the only remaining copy of a gene was inactivated through imprinting. It would be another unexplained difference.
3. Impact of a rare gene variant or partial deletion of a gene. A gene that is completely deleted can be less damaging than a gene that has an abnormal sequence of nucleotides (called a variant). An example of a dangerous variant is when a gene mutation produces cancer. Exposure to too much sun or other carcinogen leads to cells with damaged genes. Cells with damaged genes often die out. But, some may grow into a tumor. In the case of 22q13 deletion syndrome, cancer is extremely rare. However, there can be other problems when a gene is a pathogenic variant, or when a chromosomal deletion removes only part of a gene. A partially deleted gene can start creating proteins that interfere with normal cell operation (see When missing a gene is a good thing.) So, a bigger deletion could be actually be less pathogenic than a slightly smaller deletion if the smaller deletion disrupts just part of a gene. It is probably not very common, but a partial deletion or unfortunate pathogenic variant could cause of more severe problems.
4. Gene combinations. Most geneticists evaluate a deletion based on the impact of individual genes. But, current scientific studies suggest a lot more complicated things can happen when multiple genes are involved. Research in autism spectrum disorder, schizophrenia and other disorders show that these disorders are often caused when a large number of common gene variants combine together in an unfortunate way. Each variant contributes in a small way. In some cases, there are a few important genes, but they have little or no impact unless many other genes are also involved. These gene combinations are subtle and still poorly understood. Older research used the term “genetic background” to act as placeholder. More recent work has led to a newer concept called “polygenic risk”. The main genetic differences between my cousin’s daughter and my son are from our spouses, who each contributed different background genetics. Somehow, the genes from my spouse collectively lead to life-threatening problems as a newborn when mixed with his 22q13 deletion. My cousin’s daughter received a less threating set of background genes from her father.
5. Mosaicism and somatic mutations. Recent evidence shows that it is possible for a genetic error to occur in one small region of the brain. That is, some people have gene mutations that impact only certain areas of the brain. These events might explain many individual variations, including things like learning disabilities. In the case of 22q13 deletion syndrome, these silent mutations are likely to have a much more serious effect if they occur in the region of 22q13. In cases of pathogenic SHANK3 variants, the impact of SHANK3 may be greatly amplified by errors in other genes in specific brain regions. Blood tests often do not show mosaic/somatic errors that may occur deep in the brain.
6. Genetic regulators (elements). Since 2009 the ENCODE genetics project (https://www.encodeproject.org/) and others have sought to find the bits and pieces of DNA that regulate genes. Genes make up the minority of DNA. Most of DNA is comprised of gene regulators. This is very easy to understand when you realize that skin cells, brain cells, intestine cells and liver cells all have exactly the same genes. The difference is which genes are turned on and which are turned off. Skin cells know they are skin cells and only use genes necessary for the skin. Brain cells only use genes necessary for brain. The DNA is regulated in each tissue to match the needs of that tissue. Chromosome 22 deletions not only knock out genes, they knock out genetic regulators. A 4.7 Mb terminal deletion may not hit any more genes than a 4.8 Mb deletion, but it may hit a crucial regulator site. Gene regulators are not impossible to detect, but they can be difficult to study. Whole exome sequencing, a powerful tool for finding small genetic errors, skips over most of the gene regulators. Gene regulators are a likely cause of many unexplained differences.
7. Healing. DNA can be a very sticky substance. When a terminal deletion occurs (the most commonly observed occurrence in 22q13 deletion syndrome), the broken end of the chromosome can pick up various bits and pieces of DNA as it “heals” (re-seals the ends). In the extreme case the chromosome forms a ring by attaching to its opposite end. In other cases the end of the chromosome may pick up bits and pieces of DNA, sometimes copies of itself. The random junk at the end of a deletion could have an important impact, although this has not been carefully studied.
8. Positional effects. Positional effects is related to genetic regulators. The location of a gene relative to other genes and regulators on the same chromosome can be important. Enhancers, for example, are regulator elements that increase the likelihood that a gene will get used to produce its product (usually a protein). The distance between a gene and its enhancer may strongly influence how effectively the enhancer operates. Deletions, especially interstitial deletions, can change the distance between DNA elements and ultimately influence the impact of a deletion. Positional effects help explain why two similar size deletions might have noticeably different outcomes.

Final thoughts

Given the complexity and many opportunities for unexplained variation, we can begin to appreciate why knowing an individual’s deletion size does not provide all the answers. But, even with the wide person-to-person variation, studies have shown that larger deletions have a more serious impact than smaller ones. Some of my other blogs discuss specific genes and even ways to explore the influence of genes of unknown function. Parents should appreciate that it takes time to incorporate new science into medical practice. Genetic reports in the future will likely say a lot more about specific genes than reports today. If your genetic report provides a list of genes lost in a deletion, hold onto that list. Genes of “unknown significance” may someday be identified as important.

arm22q13

Some previous posts:

22q13 deletion syndrome: the hope of precision medicine
How do we know which genes are important
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
22q13 deletion syndrome – an introduction

22q13 deletion syndrome: the hope of precision medicine

Although non-verbal, David is clearly in charge of this trip.

David does not talk, but he does know how to express himself. In this photograph we are taking a ride to his brother’s apartment.  As soon as I arrived at David’s house, he grabbed my hand and walked me back to the car.  He pulled on the door leading to the back seat.  “Take me for a ride!  The usual place, of course!” He communicates very well considering all his disabilities, but I would love to have a medication to help him talk, or walk better, or toilet easier, or not overheat in the summer.  In fact, what I really want is a custom pill made for David.  Different patients with different size deletions have different needs. Although intellectual disability affects 100% of our kids and ASD affects up to 30%, the reality is that our children can have many different problems.  Except for a few confusing cases, kids with larger deletions have more problems and often more severe problems.

If you read my earlier blog on deletion size (Understanding deletion size), you will know that over 95% of patients with 22q13 deletion syndrome are missing from 10 to over 100 genes.  The genes near the end of the chromosome are the first ones to be deleted by a terminal deletion (the most common type).  These genes are tightly packed together.  In this region, you cannot simply say “a small deletion”.  You must know the exact deletion size to know how many genes are affected.

Precision medicine

According to the National Institutes of Health, “precision medicine” is “… an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person” (from: NIH Precision Medicine Initiative).  The promise of precision medicine has not reached most people because the average patient does not know which genes are most important to his/her health. For patients with 22q13 deletion syndrome, however, the genes that cause the syndrome are obviously the genes of greatest clinical importance.  The primary goal of 22q13 deletion syndrome research should be to maximize the benefit of knowing the exact genes involved on a patient-by-patient basis.  Think: “I want a pill optimized for my child”.   Of course, it is an oversimplification to think about a custom pill, but the NIH definition of precision medicine helps guide us toward more practical thinking.

In my last blog (How do we know which genes are important?) I listed the genes that are likely to contribute to hypotonia.  Categorizing the genes into  clinically meaningful categories provided us with insight into treatment.  Each gene in the list has a known effect on the brain and rest of the body.  Some genes interfere with normal brain function.  Other genes can affect peripheral myelin, a insulator that is needed to transmit information back and forth between the spinal cord and the muscles.  Still other genes can disrupt a muscle’s ability to tolerate sustained work.  Each of these categories provide important information to the physical therapist.  A child with poor sensory feedback from the muscles might be handled differently from a child with poor muscle stamina.  Precision medicine is in its infancy, used mostly in cancer treatment. However, precision medicine for 22q13 deletion syndrome could start today.  Physicians and therapists could readily benefit from a report for each person that brings together an individual’s genetics with the known functions of the missing 22q13 genes.

One might wonder how far this precision medicine idea can be taken.  Well, for next year the White House reports a 215 million dollar initiative for government supported research and promotion of precision medicine (White House Fact Sheet).  Businesses have already invested billions of dollars into electronic health records, the backbone of precision medicine. There is no question that precision medicine will bring major changes to medical practice and patient choices.

Clearing up some misconceptions

It is amusing at times to hear well-meaning parents talk about the barriers to using genetic information to guide treatment. One common misconception is that too little is known about the genes.  Actually, many of the genes have been studied for decades and the research has obvious clinical implications.  For example, at the Society for Neurosciences meeting earlier this month I talked to a young researcher from California who was working on CELSR1 (missing in about 50% of our kids).  He showed that neurons in the hippocampus essential for learning new relationships between events and places (e.g., learning to navigate a new school building or deal with a change in classroom schedule) are disrupted when CELSR1 is deleted.  What he told me next was even bigger news. A researcher in Belgium has been studying mice lacking CELSR1 for years.  It took only one email to that scientist to net a trove of information about CELSR1.  Apparently, CELSR1 is not only important for brain wiring, but also the flow of cerebrospinal fluid (CSF) in the brain. Read that: enlarged ventricles.  A radiologist who evaluates the MRI of a 22q13 deletion syndrome child will someday associate his/her findings with deletion size based on studies like these. After enough MRI reports are collected from enough patients, the association of CELSR1 with ventricle size can be confirmed.  The beauty of precision medicine is that you collect new data for the next generation each time you treat patients in this generation.  Taking your child to the doctor actually helps other patients with 22q13 deletion syndrome. Is that great, or what? For people with 22q13 deletion syndrome, it is knowing the detailed genetic information that will make it work.

Another misconception is that there is no clear relationship between deletion size and the severity of 22q13 deletion syndrome.  Actually, even if there was no clear relationship, it would still be of great value to use our knowledge of which genes are involved in each person.  But, we are sometimes faced with the confusing observation that a few kids with big deletions are more functional than others with smaller deletions.  These apparent exceptions to the rule are examples of how genetics can fool us.  Let’s use two examples to show how important knowing the basics can be.  Reading the scientific literature you can find one or two kids with tiny SHANK3 mutations/microdeletions who are more affected than one or two other kids missing a whole group of genes.  As I discussed in my earlier blog (Sometimes missing a gene is better) a gene mutation is often more damaging than deleting that gene.  Such is the case for specific mutations of SHANK3, ATXN10, CELSR1 and other genes on 22q13.  That is part of the reason I use the term “22q13 deletion syndrome”, which distinguishes deletions from mutations.  The second example is the clumping of important genes on the distal part of the chromosome. Because the genes are not evenly distributed on the chromosome, someone with a 1.5 Mbase deletion and someone with a 2.5 Mbase are actually missing the same genes.  Deletion size is not a measure of gene loss.  It simply provides a map to the list of genes that are deleted.  Comparisons have to be made after making a list of genes.

There are other reasons for a conflict between deletion size and severity of 22q13 deletion syndrome.  One recent study has shown that de novo chromosomal deletions (the most common type) often include mutations and other deletions elsewhere on the chromosome or on other chromosomes.  This more widespread occurrence of genetic errors does not tend to show up in the parents or siblings of a child with a de novo deletion.  That is, a diagnosis is 22q13 deletion syndrome raises the possibility that there are more genetic errors elsewhere in the DNA.  Precision medicine will someday not only include the deletion size, but a list of other genes that show potential issues.  There are other reasons for the unusual cases that I won’t go into, but larger deletions affect more genes and generally cause more problems. Of course, individual differences do matter.  That is why it is called precision medicine.

The future is now

My posting on hypotonia landed me an opportunity to give a guest lecture to a graduate physical therapy class.  The lecture was on the genetics of infant hypotonia.  I ended the lecture with a “hopeful warning” that all of medicine is about to change.  It was a warning, because all clinical practitioners will need to understand the implications of genetics in their practice, and it was hopeful because the lives of patients are about to get better.  It may be a while before we can go to an apothecary for a customized pill, but we can reap benefits today.  Your physicians, nurses and therapists could begin receiving guidance curated from the currently available literature on genes.  Of course, someone has to compile the information.  Perhaps we need to convene a conference that brings together experts on each gene with medical practitioners who would use the information. I have seen a number of conferences for 22q13 deletion syndrome, but none like that.

I should probably get a detailed genetic report for David and combine that with my own readings on his genes so that he can benefit from the promise of precision medicine. I am torn by a moral dilemma. I don’t want to be biased in my pursuit of 22q13 genetics. Whether we like it or not, we are always biased by what our own child needs. Not knowing David’s details is, in a way, liberating. I am hanging out with David as I write this. We are watching the Graceland video with Paul Simon.  If you know the history behind that video, it is a reminder that everyone matters, regardless of their skin color, which is to say, regardless of their genetics.

 

arm

Previous posts:

How do we know which genes are important
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

Understanding gene size

Father’s Day gifts from David

Originally posted 14 July 2015
Updated 28 March 2021
Available in Portuguese https://pmsbrasil.org.br/entendendo-o-tamanho-de-um-gene/

David has a terminal deletion of chromosome 22 caused by a balanced translocation.  Like nearly everyone with 22q13 deletion syndrome (Phelan-McDermid syndrome), he is missing a lot more than one gene.  What, exactly, does that mean?

DNA and genes

Each gene is made up of many “bases”.  DNA has two strands (strings) that grip each other tightly. Imagine a bunch of bar magnets threaded onto a string like pearls. Now, in your mind, take two of these strings and hold them near each other.  Slowly bring them close together.  When they get near, the north poles of magnets from one string will start to find the south poles from the other string. When the magnets come together, opposite poles will grab each other. Anywhere north faces north, or south faces south, that pair will repel each other until one flips around and the opposites unite.  DNA is made of chemical strings that have opposite poles. These opposites find their mate and the two DNA strands lock together. Each time a north meets a south you get a “base pair”.

Magnets can only make one type of partnership (north attracted to south).  DNA actually has two kinds of partnerships from four chemical bases.  The bases are abbreviate T, A, G and C.  T and A attract each other. G and C attract each other. If you make a string like this: -T-A-G-G-C-A-, the matching string will always look like this: -A-T-C-C-G-. That is, the strings stick to each other in this way:

-T-A-G-G-C-A-
-A-T-C-C-G-T-

Voilà! You have a small strand of DNA. This miniature DNA has 6 base pairs. The order of the base pairs describe the protein that this segment of DNA makes. The lower strand is kind of mirror of the upper strand. If you know what is on one strand you can always figure out the other strand. Thus, we now know a bunch of properties of DNA:  1) The sequence of base pairs describes how to make a protein, 2) DNA is strongly stuck to itself, 3) DNA keeps a mirror copy of itself available at all times, and 4) the length of the DNA can be measured by counting the number of base pairs. There is a lot more to learn about DNA, but this is enough to discuss gene size.

Big genes are easier to find

In a previous posting I explained that 95% of all people with 22q13 deletion syndrome are missing at least 1 megabase (Mb) from their chromosome (see Understanding deletion size). 1 Mb means 1,000,000 (1 million) base pairs along the two parallel strands of DNA. Genes are segments of the long strings, like chapters in a book. And, like many books, some chapters are long and some are short. There are 32 genes in the distal 1 Mb of 22q13, many of which influence brain function. Chromosome deletion syndromes are inherently difficult to study because so many genes are involved. It is hard enough to study and understand the impact of losing a single gene. It is much harder to study and understand 22q13 deletion syndrome, where many genes are missing.

This problem with studying multiple genes is not unique to 22q13 deletion syndrome. It shows up in neuropsychiatric disorders like autism and schizophrenia, each of which have hundreds of associated “risk factor” genes. Autism, for example, results from various combinations of these many genes (see review by Gratten et al., 2014). Chromosomal deletions are known to operate in a similar way (see contiguous gene syndrome). Each missing gene weakens the normal operation of the brain. No one gene needs to be “dominant” for the combined loss to be devastating, especially when so many brain-related genes are missing at once.

Not everyone thinks of 22q13 deletion syndrome this way. Much of the current thinking about the genes lost in 22q13 deletion syndrome focuses on one or two genes that code for synaptic proteins. The term “synaptopathy” has been used a lot recently, but that word originates from the study of the inner ear where they are able to clearly demonstrate the relationship between synaptic function and hearing loss (Sergeyenko et al., 2013). The relationship between genes and function is not nearly as clear in 22q13 deletion syndrome. Synapses are involved, but the synapse may be only one site of dysfunction (see Is 22q13 deletion syndrome a ciliopathy?). For many years no one thought primary cilia were important. Now, ciliopathies are a recognized type of brain dysfunction despite the fact that synapses are also involved. Science often goes off in a wrong direction; it is part of the process. The other thing to remember about 22q13 deletion syndrome is that it is a neurodevelopmental disorder. Something goes wrong during the growth and maturation of the brain. There are so many things that can go wrong with too few or too many neurons connecting between two sites in the brain, neurons connecting to wrong places, wrong proportions of excitatory and inhibitory neurons, etc. Human neural development is one of the most complex processes in the animal kingdom. Errors in neurodevelopment are not just problems with synapses.

There is another reason that synaptic genes have taken the spotlight. The synaptic genes of 22q13 are relatively large genes. This is the theme of our blog.

In general, large defects are easier to notice than small ones. If we look at the history of 22q13 deletion syndrome, the first cases were discovered in people with very large deletions and with the most “severe” phenotype (symptoms).  As research in 22q13 deletion syndrome advanced, smaller and smaller deletions were identified and studied. The gene that gets most attention is a large gene that has a large effect when disrupted. So, why does size matter?

Genes lost in a 1 Mb deletion of 22q13 sorted by their sizes (mRNA size).
Right click on the graph to see a full size image.

The pie chart shows the 32 genes that are missing from about 95% of patients with 22q13 deletion syndrome. The genes are sorted in order of size. The largest gene is SBF1 and the second largest is SHANK3. The genes continue in descending order of size in a counter-clockwise direction. Although the reality is a bit more complex, it is generally true that the likelihood of a gene getting accidently modified, or otherwise disrupted, depends on the gene’s size. This pie graph shows that the 10 largest genes account for half of the “protein-coding” DNA in the first 1 Mb. To put it another way, you are twice as likely to disrupt SHANK3 than it neighbor MAPK8IP2, simply because SHANK3 is twice as large. SHANK3 is 16 times larger than SYCE3. So, when studying gene disruption, SHANK3 can show up more often simply because it is big. Scientists are aware of this size effect. They have developed gene disruption scores that take into account the size of a gene (i.e., probability of loss-of-function intolerance, pLI).

As I noted above, no one has carefully studied the impact of a complete deletion of SHANK3 without disrupting other genes involved in brain development and function. It may seem surprising, but a damaged gene can actually have a more severe impact compared to deleting the gene altogether (see When missing a gene is a good thing). A pathogenic variant of SHANK3 (an atypical and harmful version of the gene often resulting from damage) can contribute to 22q13 deletion syndrome, especially when SHANK3 is the only gene affected. But SHANK3‘s contribution to 22q13 deletion syndrome when many genes are missing is remains poorly understood. There are other 22q13 genes that have severe neurodevelopmental consequences after deletion whether or not SHANK3 is involved. Future blogs will discuss some of these genes in detail.

The take-home message is that certain genes are more likely to come under the microscope (literally and figuratively) simply because they are larger genes. Being large makes a gene easier to study (usually), but it does not necessarily confer importance. Measures like pLI have been developed to separate size from importance. This measure was used in a study of Phelan-McDermid syndrome that is discussed in the blog Which PMS genes are most important?.

When a gene gets popularized in the scientific literature, lots of papers are published on that one gene, at least for a while. Scientists will focus on genes that get them grants and publications. That is how science typically works, even if it is not necessarily the best approach to finding effective treatments that families really need. The direction of science can be influenced by patient groups, but choosing the right direction requires a deep understanding of the science (the current state of research), science (the discipline) and scientists (who do science).

arm

Previous posts:
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

Understanding deletion size

David has numerous other problems in addition to intellectual disability

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?

Can 22q13 deletion syndrome cause cancer?

22q13 deletion syndrome – an introduction