PMS, IQ and why interstitial deletions matter

David is nonverbal and music is very important to him

When I was kid I took apart radios to understand how they work. This was a dangerous undertaking for a young boy. Radios were high voltage affairs in the old days. If the AC mains didn’t kill you, burned fingers from hot vacuum tubes or a soldering iron left sore spots. 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 nonessential parts continued. When done, I still had a working radio, plus a collection of spare parts. “Working” did not always mean 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. Write down which genes are incomplete in some way. A gene that is almost never incomplete gets a pLI score of 1. A gene that is often missing or major parts missing 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.

Phelan McDermid syndrome is an intellectual disability developmental disorder. The most common form is damage to the q end of chromosome 22 that leads to low IQ, language problems and coordination problems. I doubt a child without intellectual disability would be diagnosed with PMS and I doubt that a terminal deletion of 22q13.3 beyond a minimal size can occur without intellectual disability (ID). Language problems and coordination problems are common when ID is severe.

This year, a team of scientists studied all deletions greater than 50 Kb in two 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 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. (I have averaged performance IQ and verbal IQ together).

The IQ measure was designed so the median score on an IQ test is 100. A deletion that removes genes with a total pLI of 10 will shave off 26 IQ points. The expected IQ would be 100-26=74. This is not a precise measure. We don’t know if the person would have had an IQ of 75 or 125 to begin with. Both values are within the normal range of IQs. But, if the person has mild ID, the calculation has worked. The genetic result essentially explains that person’s intellectual disability. There is even an on-line tool to help do the calculation.

When we apply this tool to PMS, lots of strange things about PMS start to make sense. I will use a graph to explain. This is my first shot at explaining it. I’m sure it can be explained much better, but I hope everyone can understand at least the main points. The graph below shows how many IQ points are lost when each part of chromosome 22 is deleted. It is a prediction based on a some reasonable assumptions (which will not be discussed here). Read the graph from left to right. Or, read the graph from the top to the bottom. Both are the same. I have numbered circles to explain 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 produce ID.

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? and What do we know about PMS genes?

Circle 5: An important intellectual disability gene shows up about 8.4 Mb from the end of the chromosome. This causes a 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.

The new model for looking at chromosome deletions was not created specifically for PMS, but it seems to apply very nicely. Using this model, we should be able to estimate the exact cost (in IQ points) of a SHANK3 deletion. Current data from the longitudinal PMS study is sufficient to make this estimation. The new model can also be used to estimate expected cost of any arbitrary interstitial deletion. Finally, the new model 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 second hits. The mismatch could be used to justify more detailed testing (e.g., whole exome sequencing).

This 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 the same disorder.

arm22q13

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?
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 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

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