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genetics:interpretation:mosaicism [Retinoblastoma Wiki]
 

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Mutational mosaicism in patients with retinoblastoma

Discussion thread

Claude Houdayer (Paris)

we have a women with bilateral RB, no germline mutation found (tumor non available). This woman gave birth to two girls, each of them with a different maternal allele at the RB locus...They are now aged more than 14 and 17 years and haven’t yet develop RB.

Diane Rushlow (Toronto)

That is very interesting. That could be explained by germline mosaicism in the mother. The “mutant” allele may only carry the mutation in a small portion of her blood and germ cells. That would also explain why it was not detected in the mother.
One of our most interesting cases is a uni mother with no mutation found by sequence but her bilateral daughter carried heterozygous R455X. When we ran ASPCR specific for R455X on the mother she appeared to carry R455X at a level of about 10% of her DNA. Her second child was tested as a fetus at another lab by linkage and linkage showed that the fetus carried the same maternal allele as the affected daughter. In fact , however,our sequencing and ASPCR test showed that the second child did not carry the mutation despite carrying the same maternal allele as the affected daughter. This second child was indeed not affected. Unfortunately her third child does carry the mutation.

Claude Houdayer (Paris)

That’s amazing! 6 months ago we had exactly the same case for prenatal diagnosis: an affected father (carrying a mutation found in blood) transmitted the same allele twice (as demonstrated by indirect study) but only one of the two foetus appeared to carry the mutation. This demonstrated germline mosaicism in the affected father: accordingly, the mutant allele was at a low level in his sequence trace. Dietmar, do you have a similar case? it could be interesting to merge and publish these observations which are of special interest for the prenatal diagnostic community ?

(and just a comment for our previous case (bilateral mother): her daughters are unaffected therefore she also might not carry the mutation in her germ cells...) Hello Claude

Diane Rushlow (Toronto)

Yes it would be of interest of us to collaborate in publishing these mosaicism cases. We have quite a number of cases (about 15) where the proband is mosaic for a mutation at a very low level (in blood). To my knowledge, we only have the one mosaic unilateral mother where it has been demonstrated that the same allele has been transmitted to two children but only one carries the mutation (R455X). A third child also carries the mutation.We already have slides for this case which we would be happy to send you or Dr. Lohmann for use in a mosaicism paper. The slides show hetero R455X in the affected daughter and no evidence of the mutation in the unilateral mother by sequence; however, by Allele-specific PCR, we see a strong R455X in the daughter and a weaker R455X mutant band (about 10%) in the mother. This case has been previously been presented in collaboration with Dr. Robin Clark (who referred the family’s samples to us), in a presentation at Whistler RB symposium. This type of case has definite implications for genetic counseling, and shows the value of identifying these low level mosaics, and the inadequacy of relying on linkage studies in such cases. You refer to your case of the affected father with the low level of mutation in his sequence and the same allele transmitted to two children but only one carried the mutation. This would be a very good case for a paper on mosaicism. I think that your case of the bilateral mother with no mutation found in blood but two daughters with different maternal alleles, neither affected, might also turn out to be a low level mosaic case; mother possibly carrying a very low level of mutant cells in blood and germline. . We think that our technology is pretty good at detecting blood mosaicism. Would you consider sending us DNA from the bilateral mother with no mutation found so we can see whether we can detect a low level RB1 mutation? We have identified a number of very low level blood mosaics; some of these were later confirmed by identifying the mutation as homozygous in the tumor of the proband. If we could find a low level mosaic mutation in your bilateral mother, this would strengthen a potential paper.

 
genetics/interpretation/mosaicism.txt · Last modified: 2007/06/03 19:32 by dietmar
 
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