Which PMS genes are most important?

David sitting up Dec 2017 - small
David hanging out on a Saturday morning

What makes a gene important?

Ask anyone who has read about 22q13.3 deletion syndrome (Phelan McDermid Syndrome) which genes are most important and they will start with SHANK3, even though some people who have 22q13.3 deletion syndrome are not missing SHANK3. SHANK3 is most important for two reasons. First, mutations or deletions of SHANK3 can (although not always) have a strong negative impact on individuals. Second, a large percentage of the PMS population are missing SHANK3. Thus, SHANK3 meets the criteria of 1) potentially large impact on an individual and 2) a large percentage of the population is missing SHANK3. This blog is a closer look at all the genes that meet these criteria.

In a recent study, a group of researchers looked at genes that are highly likely to contribute to PMS and are missing in most people with PMS (Identification of 22q13 genes most likely to contribute to Phelan McDermid syndrome [full disclosure: this blog was written by an author on the paper]). That is, genes that appear to meet the same two criteria as SHANK3 for importance. What makes this study important is that it does not differentiate between genes that have been carefully studied and genes that have never been studied. We parents are not interested in gene popularity contests, we are interested in learning what is making our children sick.

I read that SHANK3 was the only important gene

Up until now, nearly all PMS research has been focused on one well-known gene, SHANK3. But, for the overwhelming majority of PMS sufferers, some 97% (see Understanding deletion size and How do I know which genes are missing), PMS is a polygenetic disorder. That is, many genes are involved. Is it possible, as a few SHANK3 scientists have suggested, that only the SHANK3 matters? Considering that people can have all the problems of PMS even with intact SHANK3 (called “interstitial deletions”), it does not seem possible that SHANK3 is the only gene that matters. (For the minority of parents whose child only has a SHANK3 variant or loss, SHANK3 is the only important PMS gene, but that strikes me as a rather selfish viewpoint.)

How can we find out which genes are most important?

There are 108 PMS genes and only 44 have been well studied. If there was no way to identify the important genes, we would be in serious trouble. Fortunately, the recent study of PMS genes was possible because of a recently compiled database of over 60,000 genomes of normal individuals (Exome Aggregation Consortium). Normal in this case means no developmental or neurological disorder. Why normal individuals? Because, this huge database lets you predict which genes can cause trouble.

Here is the trick to finding a likely gene troublemaker. Pick a gene. Look at 120,000 copies of that gene. (Each human has 2 copies, so 60,000 people = 120,000 copies of the gene.) Like anything else, some will be a little different than the others. In fact, you can estimate how many variants you would expect to occur by chance in a population of 60,000 normal people. So, for a given size gene, maybe you would expect 40 different variants of that gene in the population. What if you find only 5 variants? Something’s fishy if you find only 5. The best explanation is — here is the trick — that the other 35 possible variants of that gene cause serious problems. For one reason or another, those 35 variants removed the owners of that gene from the population of “normal individuals”. Those missing 35 variants are pathological. They cause a loss-of-function. The gene is called loss-of-function (LoF) intolerant, and those genes that are very LoF intolerant are the ones most likely to cause major health problems.

Wow! Which genes are most important?

So, which PMS genes are very LoF intolerant? That is an easy question to answer. You can go to the EaAC web site and look up any gene. Look for the row with LoF and get the “pLI” value. A value between 0.9 and 1.0 is a bad news gene. SHANK3 is 1.0 — no surprise there, but what about other genes? Let me save you some time. Below is a list of PMS genes that have a pLI value above 0.9.

Genes in this list are in the order of their position on the chromosome. The ones at the top of the list are more frequently lost in the population. If your child has a terminal deletion, look at all the genes with a Kb value smaller than your child’s deletion size. Those are the genes that most likely contribute to his/her disorder.

   Gene       Minimum deletion size (Kb) 
   SHANK3          85 
   MAPK8IP2       207 
   PLXNB2         540 
   TRABD          619 
   PIM3           854 
   ZBED4          928 
   BRD1           995 
   TBC1D22A     3,643 
   GRAMD4       4,181 
   CELSR1       4,281 
   SMC1B        5,405 
   PHF21B       5,809 
   PRR5         6,081 
   SULT4A1      6,956 
   SCUBE1       7,475 
   TCF20        8,603 
   SREBF2       8,911 
   XRCC6        9,154 

The first thing to notice is that what started out as 108 genes is now reduced to 18 genes. There are a few other genes with pLI below 0.9, but not far below 0.9. These may also be important. Regardless, the number of PMS genes has gone from intractable to something much more manageable. If your child has an average size deletion (around 4,500 kb), then there are 10 relevant genes. Note that some, although relatively few, children are missing only SHANK3.

In my next blog I will discuss what these genes do and how they might impact your child.


Previous blogs

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 modelsScience 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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