Which genes cause brain abnormalities in Phelan McDermid syndrome?

David photo 2
David has has many of the features of Phelan McDermid syndrome
Originally posted 31 December 2018
Updated 4 June 2021
Available in Portuguese http://pmsbrasil.org.br/quais-genes-causam-anormalidades-no-cerebro-na-sindrome-de-phelan-mcdermid/

Brain structure and functional abnormalities have been reported in Phelan McDermid syndrome (PMS) by a number of different investigators, including a a recent study associated with the Developmental Synaptopathies Consortium natural history study of PMS (Srivastava et al 2019). Prior studies have found abnormal formation of the cerebellum (Aldinger et al 2013), abnormal function of the cortex and amygdala (Philippe et al 2008), micropolygyria (Kurtas et al 2018), as well as commonly observed thinning of the corpus callosum and the presence of arachnoid cysts.

Brain abnormalities can provide important clues to understanding what goes wrong in PMS. They also could serve as “biomarkers”, biological measurements for early indicators of severity or evidence for treatment effectiveness. Readers of my blog will recognize that I spend a lot of time identifying which genes are most important in PMS. You need to know which genes are causing what problems to have any hope of finding effective treatments. My son, David (see picture), is waiting for new treatments. 

So, what do the brain structural studies tell us?

SHANK3 variants can impact the proper development of white matter, but have minimal impact on the gray matter of the brain (Jesse et al 2020). Gray matter is where the neurons and their synapses reside. White matter is made up of the long, thin “axons” that travel together connecting one region of the brain with another region. 

Aldinger and colleagues (Aldinger et al 2013) studied 10 subjects with PMS using x-ray images. Eight of the 10 subjects showed abnormality of the cerebellum (mostly gray matter) in addition to thinning of the corpus callosum (white matter) and enlargement of the cerebral ventricles (fluid space of the brain). Although there was no clear effect of deletion size, mutation of SHANK3 was not sufficient to cause cerebellar problems. They identified MAPK8IP2 and PLXNB2 as the more likely candidates for cerebellar malformation based on preclinical mouse studies.

The study by Philippe (Philippe et al 2008) had similar results from 8 PMS subjects. Three of the 4 subjects with small deletions (150 Kb or less) had no cerebellar or other major magnetic resonance imaging (MRI) results. The 4th subject with a small deletion had the least impressive positive finding. Thus, using MRI, there was a clear effect of deletion size, with small deletions have little or no effect. Four deletions of 1 to 9.3 Mb in size had stronger effects. Like the Aldinger study, SHANK3 did not seem to be a good candidate for most of their findings. In addition to cerebellar malformation, the group studied brain function using positron emission tomography (PET). They showed a group effect of amygdala dysfunction. Importantly, they used children with intellectual disability as their control group, a much stricter standard than other PMS studies.

The Srivastava study (Srivastava et al 2019) showed reduced size of the dorsal striatum, which is the opposite effect that loss of SHANK3 has in mouse models of PMS. Together, the results suggest that genes other than SHANK3 are driving brain malformation. SHANK3 can contribute to thinning of white matter, but is not the cause of other brain malformations.

Which genes might be driving the observed effects? Is there a smoking gun? To be a smoking gun, a gene that drives malformation should meet most, or all, of these criteria:

  1. is commonly missing in PMS
  2. has a high pLI value (see my blog Which PMS genes are most important?)
  3. is expressed in the cerebellum
  4. is strongly associated with a human neuropsychiatric or neurodevelopmental condition
  5. causes reduced brain size in the striatum
  6. impacts the amygdala

There are 6 genes on chromosome 22 that meet criteria 1 and 2. They have a high pLI score and are very frequently lost in PMS. They are located within 1 Mb of the chromosome terminus, which accounts for 95% of patients with a 22q13.3 deletion (see my blog Understanding deletion size). Those genes are: MAPK8IP2, PLXNB2, TRABD, PIM3, ZBED4 and BRD1. Of these, 4 genes meet criterion 3, being highly expressed in the cerebellum: MAPK8IP2, PLXNB2, ZBED4 and BRD1. Of these, 3 genes are associated with neuropsychiatric disorders. BRD1 is strongly associated with and schizophrenia. MAPK8IP2 is weakly associated with ASD (see my blog Which PMS genes are most associated with Autism?), and ZBED4 is weakly associated with schizophrenia. This leaves BRD1 as the strongest candidate gene for brain abnormalities/malformation in PMS.

Animal studies of BRD1 agree with the results from PMS imaging studies. Per Qvist and his colleagues in Denmark have been studying the BRD1 gene for some time. They have shown that loss of one copy of Brd1 in mice is sufficient to reduce cerebellum size, reduce striatum size and reduce the size of the amygdala (Qvist et al 2018). BRD1 is by far the strongest candidate gene for causing altered brain development, especially in gray matter.  

The importance of BRD1 in PMS goes much further than structural brain anomalies. It has been known for some time that BRD1 impacts 100s of other genes through gene regulation (epigenetics), and the role of BRD1 shifts from development in utero (fetus) to a different role after birth (Dyrvig et al 2017). Now, a new epigenetics study of people with PMS Type 1 (terminal deletions) confirms that loss of BRD1 produces widespread changes in the human genome. BRD1 is a crucial gene lost in people with deletions greater than 1 Mb.

There is little doubt at this point that BRD1 plays a crucial role in PMS. 

PMS is a contiguous chromosomal deletion syndrome, meaning that larger deletions interrupt more genes of importance. BRD1 is a critical gene for brain development. If we want to understand PMS, we need detailed studies that explore more genes like BRD1. One great way to study the impact of different genes is to look more deeply at the phenotypes and genotypes of people with interstitial deletions (PMS Type 2). A treasure trove of new information awaits these studies. Not exploring these candidate genes of PMS is a waste precious time. My son, David, and so many others, are waiting for these studies. We need to do the best possible science if we are ever going to find effective treatments.



Some selected earlier blogs

PMS, IQ and why interstitial deletions matter
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?
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
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