Poor Vincent ... What about his children?

[Function]

Hello

 

Consider the next situation which was given in a previous edition of an exam including medical genetics:

 

Young boy Vincent has fallen victim to a disease which is inherited autosomally dominantly. One gene evolved in the pathogenesis of the disease is known: KTR2. None of his parents have mutated KTR2 genes.

 

a) Which 2 phenomena are you going to explain to the parent?

b) Which are the repetition risks for the parents? And for Vincent himself?

 

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a) To me, it seems as if there's a mosaicism in the gametes of (one of) the parents. That, or the mutation is a de novo mutation. Both phenomena will be explained to the parents and this question is solved.

 

A de novo mutation, however, would impede the possibility of giving a non-ambiguous answer to the second question:

 

b) For the parents, this is easy: in our course, our professor has told us to go with 1% repetition risk for parents having a child with a genetic disease, when both of them are unaffected themselves whatsoever (intact genes).

 

But for Vincent's children, the case is much more complicated.

 

Allow me to share my points of view. I'd appreciate any feedback a lot. What do you think of my line of thoughts? Am I right? Am I missing something?

 

First consider the possibility of the disease being inhereted purely Mendelian and being evoked purely monogenetic.

The repetition risk for Vincent his children would then be 50% up to 100%, considering the cause of his disease to be due to mosaicism or de novo mutations. In both cases, a 50% risk is more realistical than a 100% risk (imagine the coincidence of 2 identical mosaicisms in the gametes of Vincent's parents, or the coincidence of 2 identical de novo mutations in his germline cells; well, perhaps not identical, but at least leading to the same problems).

 

So let's consider a 50% (to 100%) chance of repetition in Vincent's children in case of purely Mendelian monogenetic disease.

 

50% (to 100%) is, quite indisputable, the risk of Vincent passing on his affected gene(s) to his children.

 

Now, accept that the general (somewhat of a consensus) chance of repetition for a person to pass on a multifactorial disease to his children, is the square root of the prevalence in the population, and generally taken, about 3-5%.

 

Since the prevalence of the disease is not given, we must consider the chance of repetition for a person having the disease to be 3-5% for passing it on to his children.

 

But would that then be the total chance of Vincent "passing on his disease" to his children? Would that be the repetition risk for his children? The chance of passing on an affected gene is 50-100%. The general probability of developing disease in first degree blood relatives of an affected person is 3-5%.

 

Is 3-5% then the answer to the question and is that the statistical probability of Vincent's children developing the disease?

 

Or is 3-5% merely the chance in case nothing is known about the genomes of the proband and their children? Would it the be (50 to 100)% * (3 to 5)% = 1.5 to 5%?

 

Another problem arises when you consider the probability of Vincent having developed a de novo mutation: in which stage of embryology did the mutation occur? Did it occur his gametes? ... ?

 

Forgive me for mixing up the words "probability" and "chance", but that is quite irrelevant now.

 

Thanks for your insights

 

F

Edited January 21, 2017 by Function

[Function]

Nvm ... Apparently mendelian diseases are not multifactorial, and homozygotic for the dominant allele would leave him dead, so he has a 50% repetition risk for his children.