Two very recent studies of Phelan McDermid syndrome (PMS) drew exactly the same conclusion: We need to recruit and study more PMS patients with interstitial deletions if we are going to understand the syndrome (see references 1 and 2, below). This blog explains why that is a critical need. In some ways, this blog is an update to an earlier blog (Why don’t we have better drugs for 22q13 deletion syndrome?).
PMS can be broken down into a few obvious classes. The original disorder, 22q13.3 deletion syndrome, has terminal deletions and interstitial deletions. Later, SHANK3 variants (often called “mutations”) were added. As I have discussed before (Gene deletion versus mutation: sometimes missing a gene is better), mutations are a mixed bag. Some mutations produce symptoms like 22q13.3 deletion syndrome, but other mutations produce other disorders (like ASD or Aspergers), or no disorder at all.
The overwhelming majority of 22q13.3 deletion syndrome / PMS cases are terminal deletions. The smallest terminal deletions include the genes SHANK3, ARSA and RABL2B. Of these, SHANK3 was identified as the most important gene for small deletions. SHANK3 is not the only important gene (see Which PMS genes are most important?). Early on, researchers were aware that interstitial deletions have the features of PMS (Interstitial 22q13 deletions: genes other than SHANK3 have major effects on cognitive and language development). Like other deletion syndromes (e.g., 16p11.2 deletion syndrome ), no one gene deletion explains all the cases of PMS.
PMS research started out with SHANK3, but somehow it got stuck there. Being stuck has led to some serious deficiencies in our understanding of PMS. First, very little is being done for the future of children with interstitial deletions. Their SHANK3 gene is intact, so SHANK3 research does them no good. Second, drug studies that use PMS patients to study SHANK3 are likely to fail without accounting for the important genes in each PMS patient. This was discussed in the recent paper on PMS genes (reference 2). PMS patients have such a mix of deleted genes that the benefits of a drug for SHANK3 loss might not be detectable. Third, certain serious problems seen in PMS are unlikely a result of SHANK3. These issues, like poor thermoregulation (body temperature control), lymphedema, cerebellar malformation, mitochondrial problems, and certain developmental problems, impact a large proportion of children with PMS. Every year children and adults with PMS die. We need to know which genes are associated with lethality. These issues will remain serious problems for people with PMS as long as SHANK3 remains the narrow focus of PMS research. Even our understanding of SHANK3, itself, is incomplete without a much better understanding of the other important genes of PMS.
The best way to understand the many genes of PMS is to study people with interstitial deletions. They are the only PMS patients where we can safely say that SHANK3 deletion does not play a role. My last two blogs show that we actually know a lot about PMS genes that are most likely to cause problems. However, we need to know much more about how each of these genes affect people. That requires people with different size interstitial deletions.
There was one research study of people with interstitial deletions published in 2014 (Disciglio et al.). It covered 12 patients. Since that paper, there has been only one additional (single) case study of an interstitial deletion. By comparison, PubMed shows 164 papers with SHANK3 in the title. Most PMS families are probably not aware that the current major studies of PMS specifically exclude interstitial patients: Natural History of Phelan McDermid Syndrome and the Electrophysiological Biomarkers of Phelan-McDermid Syndrome. Some of the sites in these multisite studies have not excluded participants with interstitial deletions, recognizing the scientific importance of these cases. Scientifically, excluding interstitial deletion patients makes no sense. We should be seeking them out, recruiting them. As a parent, excluding interstitial deletions seems unfair to both those families, and to the rest of us. We need to get unstuck. We need the best science possible to help our children.
- A framework to identify contributing genes in patients with Phelan-McDermid syndrome. NPJ Genom Med 2017
- Identification of 22q13 genes most likely to contribute to Phelan McDermid syndrome. Eur J Hum Gen 2018
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?
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