What do we know about PMS genes?

16 Dec 2017 1 - small
Our children trust us to do the best for them
Originally posted 24 January 2018
Updated 20 April 2021
Available in Portuguese http://pmsbrasil.org.br/o-que-nos-sabemos-sobre-os-genes-pms/


In the previous blog we learned which Phelan McDermid syndrome (PMS) genes are most important. SHANK3 has often been touted as the gene that causes PMS, but SHANK3 rarely operates on its own and in some people has nothing to do with PMS (those with interstitial deletions). We learned that large studies of human populations identify 18 PMS genes that are impacted by “natural selection”. Loss of these genes are highly likely to cause problems, the problems that add up to PMS. The genes are:


The big question is, what do we know about these genes? That is, how might they be contributing to PMS? This blog is based on a paper that not only identified these genes, but also pulled together what is currently known about each. Although the paper describes each gene’s function in detail (for well-characterized genes), it also classifies genes into groups. Those groups are quite informative and help us understand why PMS has certain characteristics.

Genes that impact brain development

It is now very clear why PMS can occur with or without SHANK3. Of the 18 PMS genes that are likely to have a high impact on PMS, at least 7 impact brain development: SHANK3, MAPK8IP2, PLXNB2, BRD1, CELSR1, SULT4A1, TCF20.

MAPK8IP2 sits almost adjacent to SHANK3 and we have known for years that loss of MAPK8IP2 in mice interferes with brain function (see MAPK8IP2 (IB2) may explain the major problems with walking and hand use).

PLXNB2 regulates the growth of neurons, especially early in development. PMS is a neurodevelopmental disorder, so nothing could be more important than regulating neuron growth.

CELSR1 is also crucial for neurodevelopment. Neurons are exquisitely organized into nuclei in the deep structures of the brain and into very precise layering in the cortex. For example, pyramidal neurons of the cortex are located only in certain layers of the cortex, with the dendrites reaching upwards and the axon pointing down. The axon often winds its way towards the white matter. CELSR1 is important for orchestrating the orientation of neurons to assure proper organization.

BRD1 regulates hundreds of other genes during development. It is highly associated with schizophrenia, as well as PMS. PMS individuals with terminal deletions greater than 1 Mb are missing BRD1 and the loss of BRD1 impacts the entire genome (see https://pubmed.ncbi.nlm.nih.gov/33407854/).

SULT4A1 was recently shown to impact the mitochondria in the brain (see New science: SULT4A1, oxidative stress and mitochondria disorder). Mitochondria convert food into energy for cells. Dysfunction of mitochondria explains why deletions that disrupt SULT4A1 can have a severe impact on neurodevelopment and adult brain function.

TCF20 is a very important gene for brain function. It can cause intellectual disability and other problems on its own. It probably explains why very large deletions in PMS can be more devastating than smaller deletions (see TCF20 may explain why some big deletions are worse than others).

Genes associated with sleep

There are three genes that have close association with sleep or sleep disturbance. SHANK3 impacts sleep in some individuals with PMS, but PIM3 (see this paper) and PRR5 (see this paper) have been identified in studies that explore which genes regulate circadian rhythms (so called, “clock” genes).

Gene associated with lymphedema

CELSR1, the gene important for proper orientation of cells during neurodevelopment, is also associated with inherited lymphedema. Presumably CELSR1 influences cell orientation and the structure in the lymph system during development.

Genes that have unknown function

We must recognize that just because a gene has never been closely studied, that does not mean it is unimportant. In fact, one genomic study makes a convincing argument that genes of unknown function are just as important as the well-characterized genes. PMS has 7 genes likely to be important, yet not well-studied: TRABD, ZBED4, SMC1B, PHF21B, SCUBE1, SREBF2, and XRCC6. The first two genes, TRABD and ZBED4, are of very special concern. One copy of each gene is missing in over 95% of individuals with terminal deletions. It is imperative we find out what these genes are doing and how loss impacts PMS.


This study of PMS genes was a critical step forward in understanding PMS. It provided a short list of culprits. It explains why interstitial deletions cause PMS and it identifies where our research efforts need to be focused. Most importantly, it provides new targets for therapeutics. Unfortunately, a lot of time has gone by without any serious effort to encourage research into the full array of PMS genes. The genes listed above warrant much more study. As a parent of a child with PMS, I strongly feel we should make an effort to encourage the scientists who study these genes. It is hard to understand why so many important genes of PMS are being ignored by the PMS community.


Previous blogs

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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