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