Is 22q13 deletion syndrome a mitochondrial disorder?

David enjoying a walk in the park

Science is really interesting if you don’t let the details overwhelm you.  Scientists master huge piles of details, but they always step back to see the big picture. They are truly fascinated with science.  That fascination motivates their quest.  In this blog I will point out some really interesting facts so  you can share that fascination.

This blog is about organelles of the cell called mitochondria. If you look at cell with a high power microscope you will see something that appears to be another tiny organism living inside the cell.

Interesting fact #1: Mitochondria may have originally been single cell organisms that invaded larger cells.  Now, mitochondria are simply part of our cells.

Interesting fact #2: Mitochondria are the battery chargers of the cell. They turn sugars and oxygen into ATP.  ATP molecules are the rechargeable batteries used by the cell for nearly everything – from muscle contraction to digestion, growth and thinking.  Imagine what might happen if all your battery chargers were on the fritz. That would be a cell phone (mitochondrial) disorder with dramatic consequences.

Interesting fact #3: A paper published in January of this year shows that most people with 22q13 deletion syndrome have mitochondrial dysfunction (  Mitochondrial dysfunction affects more kids than any other problems except for intellectual and physical disabilities.

Interesting fact #4: Mitochondria are unique organelles because they operate using two separate sets of genes.  One set of genes is on the regular (nuclear) DNA.  The other genes are actually inside the mitochondria.  These genes, mitochondrial and nuclear, operate together.

Interesting fact #5: mitochondrial genes come only from the mother, whereas nuclear DNA is an even mix of both parents. The term “mitochondrial gene” is confusing.  Sometimes it means a gene from the mitochondrial DNA.  Other times it means a nuclear gene that is needed to help the mitochondria work properly.  In 22q13 deletion syndrome, a group of genes on chromosome 22 (nuclear DNA) are lost.  Many of these genes are important to normal mitochondrial function.  These are the mitochondrial genes I will discuss now.

The following genes impact mitochondria.  I have written on several of these genes previously.  This list includes the minimum size of a terminal deletion that would damage or delete the gene.  The list is borrowed from my earlier blog (How do I know which genes are missing?).

Mitochondria related gene Deletion size (Kbase)
CHKB 235.47
CPT1B 240.05
TYMP 288.47
SCO2 292.86
SELO 600.85
GRAMD4 4,180.53
TRMU 4,484.77
ATXN10 4,973.16
KIAA0930 5,577.70
SAMM50 6,821.94
TSPO 7,655.23
MCAT 7,675.07
BIK 7,688.76
ATP5L2 8,177.87
NDUFA6 8,727.69
SMDT1 8,735.12
ACO2 9,289.48

This list has 17 genes.  About half the children with terminal deletions are missing 5.3 Mbases (5,300 Kbases) or more (see Understanding deletion size).  That means half or more of our children are missing at least 8 mitochondrial genes.  Have you met a child with a really large deletion?  They generally have multiple major health issues.  It is not clear which mitochondrial genes contribute the most to their problems, but even children with smaller deletions are outside the normal range of mitochondrial enzyme functioning.

Some of these genes likely have little or no impact.  I have written about ATXN10 (Gene deletion versus mutation: sometimes missing a gene is better.). Some people inherit a mutated copy of ATXN10 that has an extra sequence.  It is an unused sequence that gets stripped off when the protein is produced.  The protein is normal.  However, the excess stuff that gets stripped off interferes with another enzyme in the body.  The interference ends up poisoning the mitochondria and killing the cells (  Fortunately, this is not a gene we need to worry about.  Our children are missing ATXN10.  They don’t have the mutated gene seen in certain families. Likewise, based on what is know about the BIK gene, it is also unlikely to contribute to our children’s mitochondrial problems.

So, which mitochondrial genes are causing so many problems?  One gene is specific for muscle function (e.g., CPT1B). We should not be surprised if that mitochondrial gene contributes to hypotonia (see 22q13 Deletion Syndrome: hypotonia). However, most mitochondrial genes are essential for normal function in every part of the body.

The degree of damage mitochondrial genes can cause can be seen with SCO2.  Loss or damage to both copies is often fatal early in life (  Perhaps more importantly, loss of just one copy of that same gene reduces essential enzyme activity and leads to behavioral defects in mice  (  Thus, SCO2 could be a major contributor brain dysfunction in many children.

We know that more than half of our kids are outside the normal range of mitochondrial function.  Many scientist believe that mitochondrial genes contribute to neurodevelopmental disorders (, and that those disorders (e.g., 22q13 deletion syndrome) are associated with mitochondrial dysfunction (for example,   What is needed now is a more complete study that includes all of our children.  How? When the scientific paper came out in January describing mitochondrial dysfunction in our children, I was certain the researchers would be invited to the 2016 conference.  The head of that study was eager to come, present his results and gather more cheek swabs. What happened?


Previous blogs

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 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: the hope of precision medicine

David, the backseat driver
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.



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

Gene deletion versus mutation (variant): sometimes missing a gene is better.

David in refrig age 4.5
David (age 4 1/2) teaching himself to
stand up using the refrigerator shelf

Originally posted 1 July 2015
Updated 21 July 2021
Available in Portuguese

Cerebellum and walking

It took David about 6 years to learn how to stand and walk. Even then, he was very unstable. I remember, if he was standing in a room and the lights went out, he would simply fall over. His balance was totally dependent on vision. He had not yet learned to use inner ears and ankle joint position sense to maintain balance. That is what the cerebellum does. It brings together the three senses involved in balance and makes rapid adjustments to our posture. Not many animals are upright walkers and most of the other ones are birds. They have wings! There is no doubt that David has problems with proper functioning of his cerebellum (including seizures associated with the cerebellum), but he did, eventually, learn to walk.

Cerebellar ataxia 10 (SCA10) and the ATXN10 gene

Ataxia is poor coordination, usually associated with walking. Drunken sailors (and others) walk with a staggered gait because alcohol affects the cerebellum. There are many different genes that can severely affect cerebellum function and thus walking. Variants of these genes produce a group of syndromes called “spinocerebellar ataxia” or SCA. Different genes cause different SCAs, each with its own characteristic phenotype.  Mutations (properly called “pathogenic variants”) of the ATXN10 gene lead to SCA10 (Zu et al., 1999). These patients have ataxia (poor gait), dysarthria (poor speech) and nystagmus (poor eye control) — all cerebellar functions. Many individuals with SCA10 also have seizures. The condition is inherited and found primarily in Latin American families (Teive and Ashizawa, 2014). The disease has a late onset (age 25 to 45) and starts out slowly. Over time, it can be totally incapacitating.

This blog is about 22q13 deletion syndrome (Phelan-McDermid syndrome, PMS). Half of all individuals with 22q13 deletion syndrome have deletions larger than 5 Mb (see my posting Understanding deletion size), and they are missing the ATXN10 gene. If I did not know more about SCA10, I would be frightened for David. He is currently between the ages of 25 and 45 and SCA10 is a frightening disease. However, it has been shown that SCA10 is not caused by missing the ATXN10 gene. Only specific variants of ATXN10 cause SCA10 (Karen et al., 2010). These rare variants of the ATXN10 gene create a protein that has gained a new function (McFarland and Ashizawa, 2012). This process is called a “gain-of-function mutation”. Don’t be fooled by the terminology. In this case, gain-of-function is a bad thing. The new function kills Purkinje neurons in the cerebellum (Xia et al., 2013).

Better off

About 50% of people with 22q13 deletion syndrome are missing the ATXN10 gene. The impact of missing this gene has never been studied on our children, but right now it looks like they are far better off missing the gene than having the rare variant found in families with SCA10.

One interesting, related observation comes from the SHANK3 gene. There is a growing body of evidence that some SHANK3 variants may be gain-of-function. Mouse models with SHANK3 mutations suggest that different mutations do very different things. (Note, the mice are genetically engineered, so it is proper to call the modified gene a mutation.)  Similar to these mouse models, in humans, different variants of the SHANK3 gene have different effects. In many cases, rare SHANK3 variants have no effect. There are people in the general population with SHANK3 variants who will never suspect their gene is unusual. Their variants are not pathogenic. Other SHANK3 variants cause intellectual disability, autism spectrum disorder or both.  It would be helpful to study human cases where all of SHANK3 is missing, but no other gene. That is the best way to examine the precise impact of missing SHANK3. Once we understand the precise impact of SHANK3, we can unravel the complex effects of all the genes of Phelan-McDermid syndrome. Indeed, that is perhaps the most important goal of PMS research.

If we want to understand Phelan-McDermid syndrome we need to understand SHANK3. Unfortunately, we are not making good use of our available data. Many of the studies I have read indiscriminately combine SHANK3 variant cases with SHANK3 complete deletion cases. That approach ignores the realities of rare variants and partial gene deletions, as explained above. I have also read papers where the authors indiscriminately combine deletions of all sizes to infer the impact of a SHANK3 deletion, without accounting for the impacts of the many other genes that contribute to Phelan-McDermid syndrome. I have written several blogs on why this approach is unsound (see PMS, IQ and why interstitial deletions matter and Which PMS genes are most important? ). What we do know is some people with Phelan-McDermid syndrome who are missing SHANK3 are more functional than some people with rare pathogenic SHANK3 variants. That strongly suggests that in some cases a person is better off missing the entire SHANK3 gene rather than having a specific pathogenic variant. Sometimes missing a gene is better.


Some previous posts:
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
22q13 deletion syndrome – an introduction