Inheritance data differences

These tables probably look familiar to most people:

Table #1

Table #2

These tables come from chapter 93 of Dr Comings' book Tourette Syndrome and Human Behaviour.

They are famous.  These two simple tables are repeated everywhere.  The reason is probably just that, they are simple.  Look at table one, then take the information over to table two and you have a nice percentage chance of a Tourette child.

Personally, I'm not sure how much I like Dr Comings...

Undoubtedly he's done more for Tourette syndrome than any other person on the planet (except of course Georges himself).  But a few things put me off about him and his work; some are personal feelings, others are accuracy ones.

Without wanting to whinge too much, I'd like to pick at this man's work for a while.  Be aware that this is written from my viewpoint.

Chapter 93: Will My Child Have Tourette Syndrome?

In a book 828 pages long, this chapter takes up only two.  Either Dr. Comings or his editors decided it would be nice if concerned parents could pick up this huge book in a library, turn to chapter 93, and find out all they wanted to know without having to borrow the book.

The only problem with this nice idea is that it hasn’t worked that way.  Dr. Comings has written 657 pages of material in the lead up to this chapter and, understandably, he doesn’t want to have to repeat himself.  This leads to a slight problem.  The information appears to be straightforward, but isn’t.

The two tables look reasonable.  They are also a good general guide.

But let’s be honest, I wouldn’t be writing this page if thought that was the best we could do.

So let’s follow what he’s done.

The first table instantly leaps out at me as being incorrect.  If you look at it critically it stops being an accurate summation of Punnett square probabilities, and actually suggests that if both your parents have 2 GTS genes you have a 200% of having at least one GTS gene.  That is, 2 out of every 1 of these people's children will have a GTS gene.  So something's a bit wrong there.

The table should look like:

Table #1

These are three very important values as we should see when we take the information from table #1 and put it into table #2.

First, however, we have to analyse the accuracy of table #2.  To avoid repeating himself too much he describes the entire process of creating the table in one paragraph.  This paragraph is often neglected when the two tables are replicated, but though brief, it hints at some very important points.

  ”…what is the penetrance of the expected set of genes?  If the child inherits no GTS genes the risk of developing TS is negligible.  If the child inherits one GTS gene, the risk of developing TS or TS-associated behaviours depends on the penetrance of the single GTS gene.  While the precise figures for this will not be available until extensive studies are completed using a DNA marker for the GTS gene, the family history studies pg650 indicate the risk for some type of symptoms is about 50 percent.  If the child inherits two GTS genes then the risk for some type of symptoms is probably very close to 100 percent.”

The first thing that leaps instantly to the front of my mind is he didn’t really know anything.  It is easy to forget that this book was written over 14 years ago (in 1990), and in the field of genetics that’s back in the infancy stage.  Being the pioneer in this field, Dr. Comings did the only thing that was available at the time, he used his family history studies for the penetrance figures.  He settles on easy numbers – 50% penetrance for heterozygotes and 100% for homozygotes.  The 100%, as he admits, is an estimate. ”probably very close to 100 percent” are his exact words.  The 50% came from his family studies, and he references them in the book (they are on page 650).  The EXACT figures he arrives at are a 48% penetrance for heterozygous males and a 59% penetrance for heterozygous females.  The correct average of those two figures is 53.5%.

There’s a problem here.

All throughout his books, Dr. Comings is adamant that 3 to 4 times as many males have Tourette’s.  He is also sure that GTS is not sex linked.  But this means his study has shown that the ratio is actually 1:1.23 not 4:1.  This means, according to his data, that females are more prone to GTS than men.

 He is still correct, but to know this you have to have read his book.

The major problem here is a definitional one.  It’s a difficult mistake to correct, and I know this because I’ve tried before.

The really really really important thing to remember is

 GTS IS NOT THE TOURETTE SYNDROME GENE!!!!

I am aware that people think it is.  I am aware that the gene was termed GTS because of Gilles de la Tourette’s Syndrome.  I am also aware that I haven’t made the distinction as clear as I should have.  I like to blame that on Dr Comings who titled chapter 93 “will my child have Tourette syndrome?” and then answered a different question.

The chapter should be titled “Will my child exhibit any of the symptoms from the Tourette syndrome or human behaviour spectrum?”  Dr Comings’ table #2 does not tell you the likelihood of a child having Tourette syndrome, it tells you the likelihood of having a child with a behavioral problem from the spectrum that includes Tourette syndrome. 

So we’ve found the major problem; Dr Comings’ data and my data are describing totally different things.  To make a fair comparison, you would have to take my data back a couple of steps.  Then we come out with reasonably similar figures.  However, I am still using different data – Dr comings used his own estimates, I have used a study by Pauls and Leckman.

In saying that though, we have hit another problem.  I have already said Dr Comings’ figures were published in 1990.   Pauls and Leckman’s study was in 1986.  So logically, when Dr Comings said the precise figures for penetrance would not be available for years, he was either unaware of Pauls and Leckman’s study or was deliberately ignoring it.

To give him the benefit of the doubt, there is a possible third reason I have recently uncovered.  In Dr Comings’ second book Search for the Tourette Syndrome and Human Behaviour Genes he describes his process for locating the GTS gene.  By the end of this book he has narrowed it down to the serotonin affecting gene TD02 on 4q31.

So Dr Comings isn't talking about the same gene I am!   It  isn't even on the same chromosome as mine!

Once again this is easy to explain.  Gene mapping is a long an arduous process, especially in 1990 before the human genome was completely mapped.  To save time, Dr Comings first looked for a likely GTS gene, then tried to disprove that this was the case (the most reliable scientific method we have).  In the time of his work, it was never disproved that 4q31 was the GTS gene.  Time passes however and now we believe that the GTS gene is at 11q23 (Merette et al., 2000).  I say "now we believe" because these things change all the time.  Tomorrow scientists may prove beyond any doubt that Tourette syndrome is caused by eating mushroom soup at age 4. 

This whole thing reinforces a very important point about all science.  It is vital all information is as up to date as possible.

Dr Comings was great in his day...now he's hopelessly inaccurate.

References

Dr Comings (1990) Tourette Syndrome and Human Behaviour
Dr Comings (1991) Search for the Tourette Syndrome and Human Behaviour Genes.

OMIM online

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