Wednesday, January 14, 2009

Exciting News: evidence of polygenetic mutation causing stuttering


Read Greg Snyder's article on his personal experience of being informed that his DNA shows evidence of polygenetic mutation: here.
Apparently, they ...  found something.  Out of all the (hundreds, if not thousands) of (stuttered blood) samples that have been taken (worldwide), they found 21 participants with a unique polygenetic mutation.  (In this case, the co-occurrence of 3 mutated genes).  I am one of the 21.  While I don’t know much of their findings, he did share that two of these three mutated genes are associated with serious (i.e., fatal) childhood diseases.  I don’t exactly know what this latter finding means, since I (along with 20 of the 21) am (are) perfectly healthy.  (For all I know, we’re all one mutated gene away from *fill in the blank*.)  In any event, they want to fly me up ... for a full work-up.  I’ll accept the offer, and keep posting about it if there’s interest. [...]
But to get the call from a world-renowned expert saying that they found something, and you are one of the 21.  That was quite surreal indeed.

23 comments:

Norbert @ BSA said...

Hi Tom

very interesting. I am not a geneticist but the first questions springing to mind is: if they've found the mutation in 21 out of hundreds of samples, how many would they expect to find in the general population, i.e. is 21 out of X amongst people who stammer any different to 21 out of X amongst people who do not stammer?

And doesn't it mean that many hundreds of other samples do not show this mutation so that would, to my lay mind, imply that there is no correlation between this genetic mutation and stammering?

Tom Weidig said...

Well, at a first order approximation, 21/X % of stutterers carry this gene mutation (where X is sample size).

So if we assume X to be 1000, we get 2.1% of stutterers. If it is 500, it's 4.2%. So lets say roughly 3 percent.

Then for the whole population it is 1% times 3% and we get 0.03% of the population. But it could also be that there are many who carry this gene combination but they never stuttered or they recovered due to other genes.

In a second order approximation, you need to look at whether the sample is biased in any way towards sex (men) or race (white males). Then the percentages will differ. For example, if it is just North European descent, then we might find more or non in Africans for example.

>> imply that there is no correlation between this genetic mutation and stammering?

Yes, that's true. But it is not surprising to me. They found many different genes for deafness. Also, this gene mutation is probably very special and easier to pick up. Others don leave many traces because they only pre-dispose to stuttering.

But this news is very important (IF PROVEN TRUE AND REPLICATED), because it shows that some stutterers definitely have genes that are clearly correlated to stuttering.

Anonymous said...

Tom -

Newsflash from the researchers tied to the Stuttering Foundation of America...

Latest Research featured in the Winter 2009 Newsletter reported by Susan Block, Ph.D.... "Social Anxiety (i.e. anxiety arising in social encounters) cannot be overlooked in the management of chronic stuttering. The evidence for a relationship between anxiety and stuttering is considerable."

WOW! REALLY??????

To me, this is a "duh" kinda moment that is so normal in SFA researchers re: stuttering -- A continuing contribution to the "dumbing down" of research in stuttering and therapies...

What a freakin' waste...

Do you ever review the SFA and its researchers or recommended therapies? Or is it all good?

Tom Weidig said...

Maybe I should. This social anxiety is also completely OBVIOUS to me and to any therapist who talked with clients.

Norbert @ BSA said...

Not sure what happened to my first two attempts to comment but here goes:

First, speaking to many people who stammer, it is completly OBVIOUS to them that their stammering was caused by enforced right handedness. Just because something appears obvious does not necessarily make it true and it bears investigation.

Re the genetics:I don't think you have addressed my two issues I have with this finding (or you have in a way that I haven't understood?): one that it doesn't tell us whether the incidence of this gene amongst the sample is any different from the incidence one would expect amongst a comparable group; and why, if it's possibly 'correlated to stuttering' does the huge majority of people who stammer don't apparently possess this gene?

"Anonymous" said...

Am I missing something about the Stuttering.Me blog that this post is excerpted from? (Or as he describes it, "isn't a blog".) ... it seems entirely anonymous. The author is not identified anywhere on the site.

The "About .Me" page does not identify him. Even his copyright notice "Copyright (c) 2009" does not, which makes no sense, since a copyright notice is only valid if it identifies the person claiming the copyright.

You say that it's Greg Snyder's blog. Why would he be anonymous?

Tom Weidig said...

Hi Norbert,

I'll leave the obvious explanation that there are obviously different degrees of obviousness to one of my next posts! :-)

Re genetics, I have to retract. Having re-read what Greg wrote, I now see what you are saying and I agree that I should make more subtle statements.

What seems clear is that Greg like 20 other stutterers have a polygenetic mutation. It is unclear whether he called Greg, because he has a duty of care to inform someone of potentially harmful genetic mutation (2 of the three can cause serious disease) or whether he called him because of its link to stuttering. It seems to me that there is more than just informing Greg, because he wants to get Greg in for further examination. He would probably not do this if there is not a potential link to stuttering.

Coming to your question, my guess is that they found an abnormally high level of polygenetic mutation in the sample of stutterers. Therefore you are asking the crucial question: Is this indeed the case?

To your second question, there are many different genetic ways to cause deafness in people. Think of a bad transport system and the genes as the building plans. The gene for road surface might be deficient, or for traffic lights, or for traffic coordination, or for efficiency of road works, and so on. Therefore I have always said that there is no single stuttering genes, but a combination of the following: single genes that cause stuttering , gene combination that cause stuttering, single genes that predispose to stuttering, and gene combinations that predispose to stuttering. So you get a lot of different genes that are only causal is a very small subgroup of stutterers. For example, in 5% the genes for traffic lights is defect, in 10% the gene combination for road repair coordination, in 15% the gene combination pre-disposing and so on. So if you select out a gene, it is very likely that you will not find it in many other people who stutter.

There are many open questions and I am sure they are working on them. As I am also not an expert, I better refrain from more speculation until I know more about the results and I have done some research.

Greg said...

For the Record--

1. I didn't put my name on the site because I didn't want it to be about me. I wanted it to be about the content and the stuttering community. But since somebody whined about it, I put my name on the about page.

2. My bet is that since this is the first time they've found a consistent polygenetic mutation associated with stuttering, they want to bring the 21 of us in because they can. Do a complete medical work-up on all of us and see if there are other trends and similarities. In other words, they could be looking for an undocumented syndrome.

Norbert @ BSA said...

Greg

"they've found a consistent polygenetic mutation associated with stuttering,"

I am not sure what the evidence is that this CPM is 'associated with stuttering' other than that it's been found in a fraction of a sample of people who stammer? Unless you take 'associated with' to have this kind of loose definition - I am not saying this isn't an interesting development but to me it's still more likely it won't led to anything.

Greg said...

Apparently the co-occurrence of this particular polygenetic mutation (i.e., all 3 genes having this particular co-occurring mutational signature) is beyond that of chance.

Believe what you want, but the researchers on this team know their stuff.

Norbert @ BSA said...

"Believe what you want, but the researchers on this team know their stuff."

I never doubted that.

"Apparently the co-occurrence of this particular polygenetic mutation (i.e., all 3 genes having this particular co-occurring mutational signature) is beyond that of chance."

Well, that's one question answered. Do you have any indication from Dennis about this?

Anonymous said...

Well I'm pessimistic (sorry about that), and I believe that nothing will come of this "exciting" news. I've heard similar news from Dennis Drayna many years ago (more than 8 years ago), and it all came to nothing. Using the car analogy, I'd like to illustrate what's wrong with stuttering research:

Let's say you bought a brand new Porsche 911. You're driving along and you notice that the engine makes a funny noise. You drive past a mechanic's workshop with the sign "Stuttering Jack's Auto Repairs - Porsche 911 Only". You can't believe your luck. The mechanic agrees to have it repaired by the following morning. Normally a mechanic has an understanding of how cars work, and can pinpoint the cause of the problem. But Stuttering Jack does things a little differently (he used to be a stuttering researcher). He has no idea how cars work, but in his workshop he has a perfect model of a Porsche 911 engine, so his technique is to compare your engine with his perfect model, and hope to find a discrepancy. He finds the discrepancy, fixes the fault, and he has another satisfied customer.

This is the same technique used by "world-renowned" stuttering researchers. They compare the DNA of stutterers with DNA of "normal humans" and hope to find a discrepancy. They have little idea of how speech develops in humans genetically - all they can do is make comparisons. But there is no such thing as a perfect specimen of human DNA; we humans are all genetically different and we all have our little mutations. The same kind of comparisons are made between the brains of stutterers and brains of non-stutterers, and again the search has been fruitless.

In science, conjectures and theories are made as to how particular phenomena occur. Then tests are devised to try and prove or disprove the theories. I haven't seen too much of this in stuttering research; it seems to be mainly all about comparisons, and this means that the researchers really have no idea.

George

Anonymous said...

For Greg, I hope and wish you nothing but the best from all the info you may find out...

But I'm wonderin'... Do their "reputations", their "pedigrees", their education -- mean to you they know their stuff?

As for this stutterer, as far as the "researchers on this team know their stuff" -- Just another group of 'snake oilers' pissin' in the wind...Here's hope it doesn't blow into you.

Tom Weidig said...

Genetics is different to much research in stuttering, because it is much more quantitative, and there are well established standard procedure. Whatever the disorder, you always have to do the same analysis and so the field has come up with stringent rules. So it is difficult for a scientist to completely mess it up. For example, once you have the DNA, you have numbers and you can play with them. And the process to get them it now done millions and millions of time and is industrialised.

George: it is true that genetics do not know the workings but that is the beauty of it. They have nothing but the DNA but still they find correlations. It is an unabiased ways of looking at stuttering. The hope is that by identifying certain types of genes you can might be able to get a better feel for what is going wrong.

Of course, I could argue that all they will find are mutation in genes responsible for speech production and we always knew that, didn't we? But still science has learned something... bit by bit...

Norbert: It depends what you mean by "more likely not to lead to something". It will not lead to a cure or something like that. It is a small piece of the puzzle. Why does this mutation lead to stuttering (if it does?)? Answering the question will bring us forward.

Norbert @ BSA said...

"Why does this mutation lead to stuttering (if it does?)? Answering the question will bring us forward."

All I'm saying is that one should be a bit more careful - at the moment all that's been found, s Greg says, that there'sa higher incidence of this gene in a small subgroup of a sample of people who stammer. We DO know from this same study that this gene has not been found in the vast majority of the sample. To me this would indicate that this gene is, at the very least, not a necessary part of an explanation of a cause of stammering.

Tom Weidig said...

We need to wait and see what the article says once it is published which will most likely take at least one year.

I disagree with your argument: "We DO know from this same study that this gene has not been found in the vast majority of the sample. To me this would indicate that this gene is, at the very least, not a necessary part of an explanation of a cause of stammering."

You cannot make this argument, because it is an unfair argument to make. Everyone already knows that there are very likely many different genes that could be involved because building a system is thousand times more difficult than a single defect like a lack of a certain protein. See deafness. So with perfect science, every time a gene is found, you will always be able to make your statement that the gene mutation is not in the vast majority of the sample. Does this then mean that genes play no role in explaining the cause of stuttering???????

In fact, the conclusion of your argumentation is exactly what I or every genetics experts would tell you: many genes can cause the same.

What is exciting here is that it is the first time in the history of stuttering that geneticists were able to pinpoint and name a specific gene (combination) that seems to correlate to stuttering.

The fact that they know have a documented case allows them to zoom into this special case. How does this lead to stammering? Why do three mutation lead to stammering and two to a fatal disease? Are there similar things happening in deafness genes? What functions do those genes have? Which proteins to they code? And so on. And so on. So it is exciting because they have something CONCRETE to work on. It is like chocolate fudge cake... when you first eat it you just cant get enough... :-)

Also, it is exciting for people who have this gene mutation, because they are the first stutterers to be able to claim that those three damn genes have to do with my stammering.

It also shifts the goal post in that all those who argue for pure psycho influence have to face the facts that at least some have genes in the background.

Norbert @ BSA said...

"It also shifts the goal post in that all those who argue for pure psycho influence have to face the facts that at least some have genes in the background."

If you say "at least some" have a genetic background then I am not sure why you quiblle about my argument that this is not a necessary part of an explanation which I took to mean that without this gene there would be no stammering.

Anonymous said...

> Of course, I could argue that
> all they will find are mutation > in genes responsible for speech > production and we always knew
> that, didn't we?

We always knew that? How? Based on what evidence? In all the years that they've been looking at the DNA of stutterers, there is no convincing evidence that any "speech production gene" is responsible. Of course there could be a genetic contribution to stuttering, but it would not necessarily be a gene that *directly* affects speech. For example, one stuttering model (the one that seems most convincing to me) suggests that the development of stuttering begins with an overactive/oversensitive amygdala; perhaps a "stuttering gene" might have nothing whatsoever to do with speech production, and may be something that indirectly affects speech. This is why I say that the method of comparing stuttering DNA with fluent DNA has been fruitless (they've been doing it for years). The "mutant gene" that may ultimately be responsible for stuttering may very well exist in a lot of *fluent people*. If they could propose stuttering models - e.g. overactive amygdala, timing during speech production, lack of coordination between the speech centres, etc. - then they could devise tests to determine the viability of the models. Tests could include looking for specific genetic traits, EMG/MRI/PET brain scans, specific hormone level tests, etc.

Tom, the more I look into stuttering research, the more I become disappointed.

George

Tom Weidig said...

>> If you say "at least some" have a genetic background then I am not sure why you quiblle about my argument that this is not a necessary part of an explanation which I took to mean that without this gene there would be no stammering.

Because you can always argue this for any multi-causal disorders. So lets assume stuttering is caused or predisposed by many different causes C1, C2, C3, C4, C5, C6, and so on. Many Cs might be genetic, others might be head injury, virus infection and so on.

For each of them, you can argue that Cx is not a necessary part of the explanation because without Cx there would be no stuttering. So at the end of the day nothing is a necessary part of the explanation. This cannot be true.

The solution is that every Cx IS a NECESSARY part of the explanation for Px% of stutterers and not for (1-Px)% for the others.

So C1 is (part of) cause for stuttering in P1% of stutterers.

C2 is (part of) the cause for stuttering in P2% of stutterers.

And so on.

And then you can group the Cs. So put all the genetic Cs together and you can say that the genetic Cs are (part of) the cause for stuttering in (P1+P2+P3+..)% of cases.

Tom Weidig said...

> there is no convincing evidence that any "speech production gene" is responsible.

I am not excluded that genes that are not directly involved in speech production involved are causing (partially) stuttering in some cases, but I would be very surprised if all genes turn out like this.

And there is not a single gene responsible.

I do not think the over active amygdala is necessary to reproduce symptoms. A normally functioning one can easily be a driver of secondary behaviours given an unstable speech initiation.

Anonymous said...

There is another thing that makes me pessimistic.

Identical twins have identical genes and it has indeed been found that if one twin stutters, the other twin has a high chance of also stuttering ... but not 100% chance (more like 70%). This indicates that environment plays a significant role. It also means that if a "stuttering gene" exists (and there's no certainty that it does), there may be many fluent people out there who have it. I wonder what would happen if somebody was able to properly test identical twins raised in different environments. I know of one test of identical twins reared apart, and the result was that stuttering was not genetic ... but that study only had a handful of cases (not conclusive).
And, if a stuttering gene exists, it does not necessarily mean that the carrier will stutter. In a recent article in the New York Times, Steven Pinker writes about having his own genome analyzed. It was found that he carries a gene that gives him a high risk of baldness ... if you look at the dust-jackets of his books, he has a lot of hair.

It's all very complicated: genes affect other genes, and they affect other genes, and so on and so on, in ways we still do not understand. Gene analysis is still a very young science and there is still a lot to learn. With all due to respect, the work of Dennis Drayna is very primitive.

George

George

Tom Weidig said...

Hi George,

I agree with you but only if environment means any non-genetic influence. Often, when people talk about environment they mean nurture, but there are many other non-genetic influences not related to nurture, parents, family or peers like accidents, illnesses, random events in the embryonic stage, and so on.

When you say that the probability is 70%, it does not exclude that some people's genes make them stutter with 100%. Imagine you have 50 with 100% impact genes and 50% with 50% impact genes, then you have a sample AVERAGE if 75%.

And yes Steven Pinker has plenty of hair.

Genetics is very difficult, but on the other hand, it is very quantitatively and easier to work with in many other aspects.

Anonymous said...

Hi Tom,

Exactly. Environmental factors come in many forms. We can crudely divide them into "internal" and "external". An example of an internal one is one where the actions of one gene affects the action of another gene, which affects the action of another gene etc. - i.e. a gene doesn't act in isolation - it is affected by other genes and by hormones. Even in the womb, a foetus may be exposed to particular hormones or chemicals that may alter (or even switch off/on) particular genes. Our present knowledge of interactions between genes is still very incomplete, but I look forward to some big improvements in coming years.

External factors are those in the physical environment - e.g family, school, neighbourhood etc. For example, if a person with a genetic predisposition for criminal behaviour is raised in a nice, caring and nurturing family environment, he may grow up to be a fine upstanding citizen, and make any purely genetic predictions look silly.

I think it's very difficult (maybe impossible) to separate the genetic blueprint from environmental factors. I believe it's wrong to say "nature versus nurture" as though they are 2 separate and opposing forces. We are not "blank slates" whose personalities are shaped only by the environment; however, our lives and personalities are not predetermined solely by a genetic blueprint. Both are needed - 1 *indivisible* entity of "nature/nurture" (just my opinion).

As far as stuttering is concerned, I really wish that there were stuttering genes that we can switch off in an embryo, and eliminate any chance of a stutterer being born. But nothing has yet convinced me that such a thing exists. As I've said previously, my current belief (which may well change in the future) is that stuttering originates due to an oversensitive amygdala, and all the secondary behaviours are learned as the child tries to consciously fight against a subconscious inhibitory response. These conscious efforts then become subconscious habits. Maybe there are genes for oversensitive amygalae, and certain environmental triggers may cause a stutter to develop.

George