After seeing the increasingly broad spectrum of MWS people on the Facebook MWS Community page, I asked the legendary Dr. Meredith Wilson about the difference between a mutation vs deletion of the ZEB2 gene.
My rather naive question:
“Does a gene mutation rather than a gene deletion mean fewer facial phenotypes, and does that mean, possibly, fewer of the classic MWS traits?”
Dr. Wilson’s very patient answer:
“It’s a bit complicated; some background: less than 15-20% of people with MWS have deletions, which take out all of one copy of the gene.
Most people with MWS, maybe about 80-85%, have mutations (changes in spelling of code) within the gene. Gene mutations are further classified into different types based on the effect they have on the gene’s protein product (nonsense, frameshift, missense etc).
Nonsense or frameshift mutations: what happens is that usually the gene stops making a full ZEB2 protein product – so there is not enough and it is like a deletion in effect.
Missense mutations: ZEB2 protein is still made at the usual amount, but it is not normal, so does not work as well.
Most MWS patients so far recognised and tested have nonsense or frameshift mutations.
In our experience most with these mutations seem to have a fairly similar range of outcomes to those with deletions (except for those with really big deletions that also include lots of other genes).
The missense type mutations are the rare ones (so far reported anyway) in MWS: only a few patients have been published. They have been milder or atypical, but it is too early for us to say missense mutation in ZEB2 always = milder effects, and we already know of at least one exception to this (a severely but typically affected person who had a missense mutation).
What we do suspect is that there are likely more people who have these missense mutations but have not been recognised as having MWS, so they have not had the ZEB2 gene test considered.
A new approach to gene testing for a person with an “unknown” diagnosis is testing many, many genes, sometimes from a selected panel of perhaps 200 genes, sometimes testing all genes.
This type of testing is expensive but gradually becoming more available. With this testing, sometimes unexpected mutations turn up in ZEB2, and then doctors get the clue that it could be MWS, go back and review features and – yes, it fits.
So we expect more people with mild MWS (or milder conditions related to ZEB2 mutations), may be diagnosed this way in future.
We are very interested in this aspect.”