Which PMS genes are most important?

David sitting up Dec 2017 - small
David hanging out on a Saturday morning
Originally posted 23 August 2017
Updated 4 June 2021
Available in Portuguese http://pmsbrasil.org.br/quais-genes-pms-sao-mais-importantes/

What makes a gene important?

If you ask someone familiar with 22q13 deletion syndrome (Phelan McDermid Syndrome, PMS), “which genes are most important?”, they will start with SHANK3. Even though some people with PMS have no problem with SHANK3, it is still the most important gene for two reasons. First, deletions of SHANK3 and many uncommon variants of SHANK3 can 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 two 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 two criteria listed above. 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. From my perspective as a parent of a child with PMS, 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

Until recently, nearly all PMS research was focused on one well-known gene, SHANK3. Some scientists have promoted the false narrative that only the SHANK3 matters. But, PMS is a polygenetic disorder. That is, many genes are involved. For individuals who have a pathogenic variant of SHANK3 and no other genetic issues (PMS Type 3), it is true that only SHANK3 matters. But, the vast majority of people identified with PMS have chromosomal deletions (PMS Type 1). Some 97% of people identified with PMS are missing up to 108 genes! (See Understanding deletion size and How do I know which genes are missing?). Consider, as well, that some people have PMS even with intact SHANK3 (PMS Type 2). SHANK3 is clearly not the only important gene. One major goal of PMS research it to identify which genes are most important.

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 independent way to identify the important genes, we would be in serious trouble. Fortunately, there is a way to predict the importance of a gene without knowing what the gene does. A large group of scientist compiled a database of over 140,000 genomes including those of “normal” individuals (Genome Aggregation Database). Normal in this case means no developmental or neurological disorder. This huge database lets you predict which genes can cause trouble. Let me explain.

There is a trick to finding a likely troublemaker gene. Pick a gene. Look at all the copies of that gene in the database. (Each human has 2 copies of each gene.) The same genes in different people are not always the same. Different people can have slightly different versions, called “variants”. It is possible to estimate (with biology and statistics) how many different variants you would expect to occur by chance in a population. For example, for a given size gene you might expect to discover 40 different variants among 60,000 people. 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 remove a person from the category of “normal individuals”. There is a name for this: natural selection. It is a principle discovered by Darwin and it works for genes.

Those missing 35 variants are pathogenic. The variation causes a loss of normal function, and the body cannot operate normally without the gene. Genes that are highly sensitive to variation are called “loss-of-function (LoF) intolerant”.  Genes that are LoF intolerant in this way are the ones most likely to cause major health problems. Only a minority of genes are LoF intolerant. Most genes tolerate all kinds of variation. Either they are less important genes, or the body has found ways to work around variations.

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 gnomAD browser and look up any gene. Look for the row with pLoF 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 (108) to something much more manageable (18 or maybe 20). If your child has an average size deletion (around 4,500 kb), then there are 10 relevant genes. Note that some children are missing only SHANK3. We will not forget them. But, in the meantime we need a major push to fully understand the other important genes of PMS.

In future blogs I will discuss what some of these genes do and how they might impact your child.

arm22q13

Some 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?
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
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
22q13 deletion syndrome – an introduction

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