I don’t know how big David’s deletion is, but he has all the hallmarks of a PMS individual with a large deletion. His developmental delays were substantial: walking took 6 years and full oral feeding required 3 more years. He is nonverbal and even as an adult it is difficult to estimate his receptive language.
Deletion size explains some of the differences between individuals, but any given individual may be far from the “average” for a given deletion size. Is deletion size unimportant? TCF20 is a PMS gene that can help explain some of the mystery.
I have started cataloging all the different factors that influence phenotype (the features of people with a disorder). The number of factors and how the different factors interplay is rather staggering. It has been known for over a 100 years that even a relatively small number of genetic factors can produce a rather wide spectrum of phenotype characteristics. “Phenotype variability” is the term used to describe the diversity. As I progress on the cataloging of what causes phenotype variability in PMS, I will blog on various aspects and examples.
This blog is on TCF20, an important PMS gene that is lost in large (over 8.6 Mb) terminal deletions and some interstitial deletions. I mentioned that TCF20 is an important brain development gene in an earlier blog (What do we know about PMS genes?). TCF20 has all the characteristics of an important gene based on several different studies. At the time I wrote that blog I did not notice a paper (Prevalence and architecture of de novo mutations in developmental disorders) in Nature, a top scientific journal. In that study, the authors were able to affirm TCF20‘s role in genetic disorders. The cases they studied were not PMS, with large deletions. These cases were de novo mutations. Their results show that loss of TCF20 function can, on its own, cause a developmental disorder. It is yet another reminder that a number of PMS genes can cause disorders on their own, without any involvement of SHANK3.
This blog is about phenotype variability. TCF20 provides not one, but two examples of variability. These two factors operate together to explain why some kids with large deletions are more impacted by deletion size than other PMS kids.
Large deletions that are almost the same size can be very different from each other. An 8.5 Mb deletion does not impact TCF20, whereas a 8.6 Mb does. We can be confused about the impact of deletion size if we do not look closely at the genes. That is the first factor: a small change in deletion size can have a large effect. Note that the opposite can also be true. In some locations on chromosome 22, large changes (500 kb or more) can be unimportant.
The second factor is a bit more subtle. A recent paper has affirmed something else about TCF20. TCF20 is especially sensitive to “genomic imprinting” (Genome-wide survey of parent-of-origin effects on DNA methylation identifies candidate imprinted loci in humans). Normally, either copy of a gene is used by the cell. Genomic imprinting is when only one copy of a gene is used by the cell. The other copy is permanently turned off, never used. Consider this, if someone has a large deletion, but the deletion removed the copy of TCF20 already turned off, the deletion will have no effect on the production of TCF20 protein (a transcription factor). On the other hand, if the large deletion removed the active copy of TCF20, no TCF20 protein will be produced by the cell. Thus, for TCF20, “genomic imprinting” can determine whether deletions over 8.6 Mb are more devastating than smaller deletions. The two factors, deletion size and genomic imprinting, operate together. We cannot predict the effect of one without understanding the other.
Very few PMS genes are subject to genetic imprinting, but this story serves as an example. We have the scientific tools to explain phenotype variability. There are cases where deletion size seems unimportant, but these cases can be explained. The many factors that influence the future of a baby with PMS are not magical. Many people have overestimated the role of SHANK3 because PMS phenotype variably seems so mysterious. Genetics are complicated, but not mysterious. TCF20 provides a great example of how applying the science carefully can uncloak some of the mystery.
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?
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