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.







Have you ever met a child like mine?

Sometimes, David likes to be held.
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.




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


22q13 deletion syndrome: How do we know which genes are important?

David resting

Facebook like

When I get on Facebook I look for pictures of our 22q13 deletion syndrome kids.  Every time I see one I give it a “thumbs up”.  It warms my heart to see other parents share their pride in their children, even if our children are peculiar in some way.  Our snapshot may capture a funny posture or gait.  David is almost always looking away from the camera.  Some 22q13 kids are captured chewing on “non food items”.  We post photos to show our pride in accomplishments that would have been easy for most other kids.  Our children are usually not very photogenic, except to families and, of course, other parents of kids with 22q13 deletion syndrome.

There are some pictures that we don’t put on Facebook in deference to families that could not appreciate them.  There are pictures of feces on the sofa, self-inflicted injuries, frightening hospital scenes, and even pictures after an early death. The reality of 22q13 deletion syndrome is often not pretty.  However, our goal is not to provoke a reaction. We simply want to share joy or commiserate with our community, like all parents.

David, like the overwhelming majority of children with 22q13 deletion syndrome, has many things wrong.  He is missing more than one or two genes and the impact is pretty obvious.  Ninety-seven percent of children with terminal deletions are missing from about 30 to 200 genes (see Understanding deletion size).  Science can help us find ways to help our children.  The first step is to find out which gene causes which problem.  Fortunately for our children, science has a bunch of relatively new tools to help create this “genotype-phenotype map“.

First things first.  Let’s have a look at the list of genes that are lost with a 22q13 terminal deletion (the most common type of deletion).Genes lost in 22q13 DS

This is a list of genes organized by deletion size.  The deletion size on the left corresponds to the list of missing genes of the same color on the right.  A 1 Mb deletion will delete all genes in dark brown, starting from RABL2B and ending with ALG12 (33 genes).  The next group (reddish brown) are missing if your child has terminal deletions of 5 Mb or more (16 more genes, giving a total of 49 genes).  That covers about half of all common terminal deletions.  Terminal deletions have been observed for sizes up to about 9 or 10 Mb.  The genes above that are usually missing only with certain interstitial deletions.

Ok, so now we have our list.  The crucial question is, which genes do what?  In the past few years scientists have built some rather clever and remarkable tools for figuring this out.  Here are some tools and some examples of how they can be used.

Comparing 22q13 genes with known genetic syndromes

Online Mendelian Inheritance in Man (OMIM) is a database of genes and the problems associated with them.  By choosing a trait like poor body temperature control (poor thermoregulation) or low muscle tone (hypotonia), you can find out what genetic disorders have that feature.  From that information, you can identify which genes are involved.  Sound complicated?  Not at all. If you go to the Human Phenotype Ontology web site and type in “abnormal muscle tone” it does the entire cross-reference in a few seconds.  Click the tab for “genes” and you get a list.  I did just that.  I found which genes match the list of 22q13 genes and highlighted them here.

What is interesting about this list is that only two genes are directly involved with the synapses of the brain (SHANK3 and MAPK8IP2).  Other genes linked to hypotonia have other important functions. One gene is important for the synthesis of neurotransmitters (SULT4A1). Some genes affect white matter and peripheral nerves (ARSA and SBF1).  Another gene affects the muscles directly (CHKB).  Some genes affect many organs (ALG12 and NAGA).  As I see it, each gene is an opportunity to find a treatment for our children.  If one gene is complicated and hard to study, there are other genes that might lead more quickly to important benefits, like new treatments.

Comparing 22q13 genes with genes that work specifically in the brain

If we are interested in behavioral problems and intellectual disability we can benefit from a recent scientific study that has created a list of genes that are specialized for the brain (Pandey et al., 2014).  Using a “gene expression atlas,” these researchers identified genes that are either used (expressed) at a very high level in the brain, or used much more in the brain than anywhere else.  The logic is simple, if the brain treats these genes as important, then they must be important.  Genes lost - Brain

Only 4 genes show up.  These are obviously 4 genes that deserve careful research to help people with 22q13 deletion syndrome.  Two of these genes, MAPK8IP2 and SULT4A1 also appeared in the hypotonia gene search.

Comparing 22q13 genes with genes that evolved for a specific purpose

One of the most interesting new methods for understanding the role of genes comes from the study of how humans evolved.  I have already written about the value of this approach (see Is 22q13 deletion syndrome a ciliopathy ?).  There is an interesting website that automates the process of studying evolution. This approach, called “forward genomics” is more difficult to use than the previous two examples, but this method may solve some important problems.  I am very interested why David gets too hot in the sun and too cold after a bath.  That is, why does he have problems regulating his body temperature.  By studying the scientific literature on which animals are good at body temperature regulation and which animals are not, this web site will tell me which genes are involved.  My job is to read textbooks and papers to find out how well each of 27 species of animals regulate their temperature.  Once I do that, I can ask the website to scan the genomes of these species and identify which genes are associated with the emergence (or loss) of the ability to regulate body temperature. It is a fascinating approach and I am very eager to learn the results. The results may open the door to lowering the risk of febrile seizures.

Other methods

There are other methods for finding genes that affect our children in specific ways.  For example, gastroesophageal reflux was such a serious problem for David that he required major abdominal surgery (Nissen fundoplication).  A comparison of reflux with known genetic conditions (similar to the hypotonia example) provided no new information about 22q13 deletion syndrome genes.  However,  the search did produce a list of 48 reflux genes. How can we use the reflux gene list to learn more about 22q13 genes?  First, there is an analysis method called “guilt-by-association“.  This analysis will indicate which 22q13 deletion syndrome genes naturally operate in concert with the reflux genes.  A even more complex analysis tool for protein-protein interaction can identify which 22q13 genes have chemical interactions with reflux genes. I expect one or more 22q13 deletion syndrome genes will be associated with reflux after these analyses.

Tremendous progress has been made in the understanding of how genes contribute to disorders.  The best way science can help our children is by identifying the many different genes that cause the many different problems.  That is Step One and modern methods make that step much easier and more informative that the old methods of the past.  Step Two is to find treatments.  Many of these genes have been studied in great detail.  Some have related treatments either already in use or suggested by researchers.  As a parent, I want to see new treatments found for David.  As a researcher, I don’t understand why we are not taking these potentially fast tracks to treatment.



Previous posts:
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

22q13 Deletion Syndrome: hypotonia

Walking with David
A Sunday walk with David
Originally created 29 August 2015
Updated 28 November 2021
Available in Portuguese

The joys of walking

Although he is a bit unsteady at times, David loves to walk. David began a day program after high school and he was assigned an aid new to the program. After one month the aid nearly quit! Keeping up with David’s constant motion — usually walking — forced the aid to become an athlete. After working with David for twelve years, she looks back at the experience in an appreciative way. David brought fitness into her life and the two of them developed a deep affection for each other. They enriched each other’s lives in many ways. Health from walking was an important one.

David has 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome (PMS). David, like many others with PMS, was born a “floppy baby”:  A general medical reference to an abnormal condition of newborns and infants manifested by inadequate tone of the muscles. It can be due to a multitude of different neurologic and muscle problems. See also Hypotonia. At age one, after daily work-outs and multiple physical therapy sessions each week, David developed the strength to lift his head and arms. He gradually learned to sit up, drag himself by his arms, and then crawl. Countless hours of therapy in a clinic and at home went into each milestone. We pushed him constantly for six years. Each time he improved, we “raised the bar”. Once David gained strength and basic skills, his mom, Carol, would exercise David at the grocery store by having him hold onto the side of the shopping cart as she pushed. One day, fascinated by a stack of bright red apples in the produce section, David let go of the cart and walked eight steps on his own to reach the stack of applies. Carol was caught completely by surprise. David reached the apples and everything ended up on the floor. The store staff came running and found Carol holding David, crying tears of joy. After six very long years, David had learned to walk on his own. Now, David I go on weekend walks together (see photo). Every time I walk with David, it warms my heart to watch him


Having very low muscle tone interferes with normal growth and development in many ways. Muscle tone is important for breathing in newborns (Lopes et al., 1981). David was born prematurely and he was on a ventilator for weeks. Low muscle tone slowed his recovery. Muscle tone is important for normal cognitive development and function (e.g., Jongsma et al., 2015). Gastroesophageal reflux plagues many children with PMS (including David) and is likely caused by low tone of the esophageal sphincter (Hershcovici et al., 2011). Other gastrointestinal problems likely result from muscle tone problems of smooth muscles. The most obvious problem with low muscle tone, however, is delayed or absent walking. Walking requires stable standing, which requires sufficient tone to hold the body erect. Building strength in David’s abdominal, back and leg muscles took years of work.

What is muscle tone and what interferes with normal tone? For skeletal muscle, “Muscle tone refers to the resistance that an examiner perceives when moving someone’s limb in a passive manner” (Mitz and Winstein, in Neuroscience for Rehabilitation, 1993). Normal muscle tone disappears when someone is knocked unconscious, or when the muscle itself is unable to support contractions. Diagnosing the cause of hypotonia in infants can be complex, especially in the presence of a genetic syndrome (Bodensteiner, 2008). In genetic syndromes that include both hypotonia and intellectual disability, the hypotonia is often diagnosed as “central hypotonia”: hypotonia caused by problems with the brain or spinal cord. However, the hypotonia associated with PMS may be from multiple causes. Certainly, it is not caused by any one gene. No single gene deletion or mutation has been identified that always causes hypotonia, and no one gene is essential for hypotonia. There is also no doubt that infant hypotonia is far more common in children with somewhat larger deletions (Sarasua et al., 2014, figure S1).

The severe hypotonia so often seen in infants with PMS may arise from multiple sources. Since finding ways to treat hypotonia could help children with PMS, understanding the causes will open the door to improving their lives.

Genes that directly affect synapses 

If your child with PMS was seen by a pediatrician or pediatric neurologist, it is likely the physician concluded that the hypotonia was of central origin (see, Bodensteiner, 2008). Although the conclusion would be based on accepted clinical practice, it would actually require a battery of tests to rule out other sources. Without other signs of major muscle or metabolic problems, the physician may be wise to avoid the additional tests that would be necessary. Right now, such testing is best done as part of a research study.

Which genes might contribute to low muscle tone of central origin? One obvious source of central hypotonia is a problem with synaptic proteins. For chromosomal deletions of 22q13.3, two proteins coding genes are nearly always deleted together: SHANK3 and MAPK8IP2. I have found only one published clear case where MAPK8IP2 and more proximal genes were deleted without impacting SHANK3 (Vondráčková et al., 2014). That patient had hypotonia. Thus, hypotonia can be caused without impacting SHANK3. What is lacking in PMS research are more studies of children with so called interstitial deletions. (See my blog: PMS, IQ and why interstitial deletions matter). Generally, hypotonia created by the deletion of SHANK3 is less than with deletions of any larger size. If we include pathogenic variants of SHANK3, we know that hypotonia with a SHANK3 variant is much less prevalent (33%) than hypotonia in patients with terminal deletions of 22q13.3 (65% to 75%), whether or not SHANK3 is involved in the deletion (Vondráčková et al., 2014).

Genes that affect brain development

In PMS, hypotonia of central origin is likely caused by the genes essential to normal to brain development. A review of PMS genes showed that 18 genes that are deleted in PMS patients are associated with brain development (Mitz et al., 2018). Of these, 10 genes are associated with reproductive fitness (e.g., necessary for normal health) based on their “pLI” scores: SHANK3, MAPK8IP2, PLXNB2, TUBGCP6, BRD1, TBC1D22A, CELSR1, SULT4A1, TCF20 (see Supplementary Table S2 of Mitz et al.). Since that study, The gene PHF21B has been added to the list as an epigenetic regulator of development (Basu et al., 2020). Thus, genes across the nearly entire 22q13.3 region associated with PMS are critical genes that participate in normal brain development. Any, and likely all, contribute to both the intellectual disability and the hypotonia of PMS.

Genes that may affect the environment of the central nervous system

We sometimes forget that the brain must have lot of things working properly for synapses to operate. For example, the brain is about 2% of our total body weight, but it uses up 20% of the oxygen we breathe (Rolfe and Brown, 1997). So, the blood flow from the heart, nutrition from the gut and oxygen from the lungs are of critical importance to human brain function. Any missing gene that might affect the brain’s ability to process energy in the mitochondria may impact synaptic function. Note that studies of rats and mice might be misleading. The rat brain, for example, uses only 3% of the oxygen they breathe for brain function. These mammals are not nearly as sensitive to the “energetics” of brain function as humans. The genes of 22q13.3 used by mitochondria appear to have a mixed impact on people with PMS (Frye et al., 2016). Beyond hypotonia of central origin, the same genes that affect the energy supply for the central nervous system can affect muscles directly. Muscles come in three flavors, skeletal, cardiac and smooth. They are all major users of energy.

SCO2 and TYMP are two mitochondrial PMS genes that are lost with relatively small deletions of 22q13.3. Individuals missing one copy of SCO2 and/or one copy of TYMP seem to do fine (Pronicka et al., 2013). However, if the remaining copy of either SCO or TYMP has an unusual variant, the results can be profound (Vondráčková et al., 2014). Of greater concern for most people with terminal deletions of 22q13.3 is the SULT4A1 gene. SULT4A1 is one of the few genes that has been implicated in intellectual disability and hypotonia based on a study of interstitial deletions. Recently, it has been shown the SULT4A1 protein is crucial for mitochondria function in the brain.


Most clinicians will conclude that hypotonia in children with PMS is of central origin. This is a good assumption, but further research is needed to look for more direct effects on muscle. There is strong evidence that many PMS genes contribute to central hypotonia, and central hypotonia occurs with all genotypes of PMS (see The four types of Phelan McDermid syndrome). On average, larger deletions lead to greater hypotonia. Developing broad and effective treatment for hypotonia will require understanding more about each gene’s contribution to maintaining healthy muscle tone (see 22q13 deletion syndrome: the hope of precision medicine).


Understanding deletion size

Side glance
David has numerous other problems in addition to intellectual disability
Originally posted 4 June 2015
Updated 1 April 2021
Available in Portuguese

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.)

how many patients and how many genes

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!


Previous posts:

Can 22q13 deletion syndrome cause ulcerative colitis?

Can 22q13 deletion syndrome cause cancer?

22q13 deletion syndrome – an introduction