Which genes cause brain abnormalities in Phelan McDermid syndrome?

David has has many of the features of Phelan McDermid syndrome

Brain structure and functional abnormalities have been reported in Phelan McDermid syndrome (PMS) by a number of different investigators, including a brand new 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), 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. So, what do the brain structural studies tell us?

The Aldinger paper studied 10 subjects using x-rays images. Eight of the 10 subjects showed abnormality of the cerebellum in addition to thinning of the corpus callosum and enlargement of the cerebral ventricles. 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 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 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 new Srivastava study showed reduced size of the dorsal striatum, which is the opposite effect that SHANK3 has in mouse models of PMS. This result strongly suggests that other genes are driving the losses in these deep forebrain structures.

If SHANK3 is not the cause of the measured brain malformations, which genes might be driving the observed effects? Is there a smoking gun? To be a smoking gun, the gene should meet 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 condition
5. causes reduced brain size in the striatum
6. impacts the amygdala

There are 7 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 Mbp of the chromosome terminus, which accounts for 95% of patients with a 22q13.3 deletion (see my blog Understanding deletion size). Those 7 genes are: SHANK3, MAPK8IP2, PLXNB2, TRABD, PIM3, ZBED4 and BRD1. Of these, 5 genes meet criterion 3, being highly expressed in the cerebellum: SHANK3, MAPK8IP2, PLXNB2, ZBED4 and BRD1. Of these, 4 genes are associated with neuropsychiatric disorders. SHANK3 and BRD1 are strongly associated with autism spectrum disorder (ASD) and schizophrenia, respectively. 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 two strong candidate genes, SHANK3 and BRD1. Interestingly, SHANK3 is weakly associated with schizophrenia and BRD1 is weakly associated with ASD.

Which of these two genes are responsible for the structural deficits seen with chromosome deletions? Perhaps the answer will come from the last two criteria. As noted earlier, SHANK3 is associated with increased brain size of the striatum, not reduced brain size. That could be a strong indicator, as well as the fact that SHANK3 mutations do not consistently cause the structural deficits seen in patients with 22q13 deletions. In addition, SHANK3 is not known to have a major impact on the amygdala, a structure important for making social judgements. What about BRD1?

The answer comes from a paper released this past November, Brain volumetric alterations accompanied with loss of striatal medium-sized spiny neurons and cortical parvalbumin expressing interneurons in Brd1+/− mice. Per Qvist and his colleagues in Denmark have been studying the BRD1 gene for some time. In this recent paper they show loss of one copy of Brd1 in mice is sufficient to reduce cerebellum size, reduce striatum size and reduce the size of the amygdala. BRD1 is the only gene that meets all the criteria. BRD1 appears to be the smoking gun.

PMS is a contiguous chromosomal deletion syndrome, meaning that larger deletions interrupt more genes of importance. David is missing a chunk of chromosome 22 and is severely impacted by PMS, a hallmark of deletions compared to mutations, as several studies have shown. If we want to understand PMS, we need detailed studies of patients with interstitial deletions to learn more about genes like BRD1. Otherwise, we are wasting precious time.

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

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