For years I have looked for a simple way to explain Phelan McDermid syndrome (PMS) to David’s caregivers. What is it and how does it happen? Here is my latest version.
What is PMS?
Since the overwhelming majority of PMS cases include intellectual disability, we can use the following definition to help explain PMS (see additional note #1). PMS requires:
- A chromosome deletion in the region called 22q13, and/or disruption of the SHANK3 gene also in that region.
- Intellectual disability (IQ less than about 75 (see additional note #2))
How does the deletion in 22q13 cause intellectual disability? Take the IQ that came from the parents, subtract the IQ loss from the SHANK3 gene disruption and the loss from the other genes that are deleted (see this blog for the science). If the resultant IQ is below 75 or so, the person has PMS.
The main problem with this formula is that we don’t know what IQ a child would have without PMS. Future research might make it possible to know, but we don’t know now. We also don’t know exactly how many IQ points are lost with SHANK3, but we might have that number soon. Even with these problems, we can use the formula to get a better understanding of what causes PMS. Here are some very instructive (made-up) examples.
Examples
Example 1: interstitial deletion near SHANK3, but SHANK3 unaffected
Above average IQ from the parents = 116
Loss from SHANK3 = 0 (SHANK3 is not affected)
Loss from 1 Mb interstitial deletion = 25
116 – 0 – 25 = 91
ANSWER: Not PMS (an IQ of 91 is within the normal range)
Example 2: 6 Mb interstitial deletion, SHANK3 unaffected
Average IQ from the parents = 100
Loss from SHANK3 = 0 (SHANK3 is not affected)
Loss from 6 Mb interstitial deletion = 50
100 – 0 – 50 = 50
ANSWER: PMS (an IQ of 50 is mild to moderate intellectual disability)
Example 3: Terminal 1 Mb deletion (SHANK3 is completely removed by a terminal deletion)
Average IQ from the parents = 100
Loss from SHANK3 deletion = 40
Loss from 1 Mb deletion = 25
100 – 40 – 25 = 35
ANSWER: PMS (an IQ of 35 is moderate to severe intellectual disability)
Example 4: 6 Mb terminal deletion (9 Mb is the largest, 4.5 Mb is the average size deletion)
Average IQ from the parents = 100
Loss from SHANK3 deletion = 40
Loss from 6 Mb deletion = 50
100 – 40 – 25 = 10
ANSWER: PMS (an IQ of 10 is profound intellectual disability)
These are not intended to be “real” cases but they could happen and do illustrate the cumulative loss of several or many important genes.
Conclusion:
In most cases, PMS is not complicated to understand. From these examples, we get an idea of what must be done to overcome the intellectual impact of the syndrome.
Additional notes
- There is no universally-agreed upon definition of PMS, but most PMS researchers readily agree in most cases. It seems possible that someone can have IQ in a normal range, but still have PMS. That might occur if someone has another major feature of PMS, like severe hypotonia or significant expressive language problems.
- IQ has different ranges. The threshold for intellectual disability (ID) can be different from the threshold for normal (average IQ). Normal range is above 84. “Borderline IQ is 70-85”. ID is sometimes considered anything below 75, but below normal is anything below 85. This blog is not a diagnostic manual, so no one should use the numbers as a substitute for professional testing, diagnosis or treatment.
- No one yet knows the exact loss of IQ associated with SHANK3 deletions The value assumed here is 40, which is not unusual for high penetrance genes. Data from PMS patients, especially data from interstitial deletions, will help determine the exact value.
- Note that interstitial deletions can cause PMS, or not, depending on the severity of the deletion. There are a few people who disagree with this part of the definition.
- SHANK3 de novo mutations (also called variants) can cause PMS, but there are clear examples where the exact same variant causes PMS in some cases, but not others. This may be the result of the initial IQ of the individual. We assume average IQ of 100 for some of the examples, but actual IQ in the general population can commonly be from 85 to 115. Some SHANK3 variants may have little or no impact on IQ. Other variants may have additional serious consequences (called gain-of-function variants).
- Chromosome 22 terminal deletions are obviously quite impactful. They remove all of SHANK3 and lead to major IQ losses from the rest of the deletion. This is how PMS was discovered in the first place.
arm22q13
Some selected earlier blogs
Which genes cause brain abnormalities in Phelan McDermid syndrome?
PMS, IQ and why interstitial deletions matter
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?
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
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
22q13 deletion syndrome – an introduction
arm22q13 
With regards to our Son Henry, the “analysis shows a deletion of chromosome 22 encompassing 146 probes located within the long arm at 22q13.31.q13.33. The deletion is estimated to be between 4.71Mb – 4.77Mb deletion and appears to include probes at the terminal region. The gene SHANK3, included in the deletion seen in Henry, etc.”
Therefore using your table, I used Example 4, what would the value of the loss be for Henry’s 4.74 deletions? Should I assume that value to be a 50 value loss in IQ?
Kind Regards, Stuart
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If you go back to the earlier blog, “PMS, IQ and why interstitial deletions matter”, you can look up the estimated IQ loss on the graph. At 4.7 on the graph (X axis), the IQ loss (Y axis) is about 70 points. The graph was made with slightly different assumptions about the exact values, but a 50 to 70 point IQ loss is the general prediction. I certainly cannot address your son’s performance, but it is disturbing for me as a parent to see these large numbers. Note that 4.7 Mb just happens to be an average size deletion.
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Thank you Arm, Henry was diagnosed in 2016, and will soon be 13 years old. So his diagnosis was when he was 10. As you have experienced that lack of diagnosis is just like being in the dark. Thank you very much for being there for us.
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