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Germline Mosaicism

Beth
0 Recommendations

I had some interesting information with a genetic counselor and
geneticist this morning. They recommended that both of my other
children be tested for VHL, even though my husband and I are negative
because of "germline mosaicism." This is how it was explained to me:
Because we have one child who has VHL, and both parents are negative,
Steven's case (our son with VHL) is very likely a new mutation.
However, there is a small, small (4%) chance that Steven got VHL
through germline mosaicism. It is possible that my husband or myself
carry the VHL mutation in sperm or eggs, but that is the only place in
our bodies where the mutation occurs. If Steven got VHL through
germline mosaicism, not new mutation, then the other children also have
a chance of having VHL.
I, like most, have always read or heard that if the parents are
negative there is no reason to test the other children.

Any input on this?

Bangotti
cross-posted JWG

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8 replies

Beth

It's true; Germline mosaicism is possible. Mosaism means that not all of
your cells carry the same genetic information. This would most likely be due
to a mutation that occurred after the initial conception.

Just after the sperm and egg fuse that one single cell divides to become 2
different cells, both of which divide to become 4 different cells, which all
divide to become 8 different cells, and so on and so on. Any genetic
information in the original cell is carried on and conserved in each new
cell that arises. BUT, if a mutation occurs, it is also preserved and passed
along to each new cell. Here's how mosaicism happens. If a mutation occurs
at the developmental stage when there are multiple cells and a mutation
occurs in one of them, then only that one cell will continue to pass along
the mutated gene. This makes for a situation where only a fraction of the
cells in your body contain the mutation. For example, if the mutation
occurred at the stage when someone was only 8 cells, then only 1/8 of your
cells would contain the mutation since only the cells arising from the
affected cell would be affected.

I hope this helps explain what mosaicism is. It basically means that you or
your husband may have VHL but only have the mutated gene in some of your
cells. This is why you could have passed a VHL test; because the DNA they
tested could have been from a cell that did not have the mutation.

Christina
cross-posted JWG

Beth

Christina,

Just curious, does this mean someone can have a negative VHL test, but then
still go on to have VHL problems in the affected cells? I remember someone a
while back saying they'd had a negative test, but were still convinced they
had manifestations of VHL. Interesting stuff!!

Maria
cross-posted JWG

Beth

Most likely we're not even testing this person for VHL unless...

(1) they already have a VHL issue, or

(2) they have a child with VHL

All of the VHL tumors occur by themselves in the general population, so if there is only one kind of tumor, it might also be one of those random sporadic tumors.

We had two men some time ago who had full-blown VHL and were the first in their families. Both sets of parents were tested and all four were negative for VHL.

Then a few years later, the fathers of both these VHL patients came down with pancreatic cancer. Might these two fathers have been mosaic for VHL? We can't know for sure, but it's an interesting notion.

Best wishes,
Joyce

Beth

I am a mosaic. My blood has tested negative, but I have had an angioma in my eye, a tiny tumor on my spine, renal cell cancer in both kidneys, and a tumor on my pancreas. My sons were recently tested and one has tested positive, which also confirms my diagnosis. So even if you are suspected of being a mosaic, it is important to test all areas.

Charlotte65

I'm puzzled myself. I thought I had something in my eye which led to the discovery of blastomas there. Since I' ve had part of my left kidney removed with tumors there. and I've got small "nodules" in the brainstem and spine not causing too much trouble at the moment...
My DNA has been tested but nothing found, a tissue sample from the removed kidneypart has come up with nothing..
I have three kids, as of yet no symptoms but DNA testing is not advised/possible because they don't have my "mutated2 DNA to compare with. All my kids have yearly eye check-ups and my oldest daughter (17) has her urine and blood tested too once a year.

I'm the forst in my family.
If it was a mosaic, is it not strange it affects both eyes, kidney brainstem and spine?

Regards
Charlotte, UK

joyceg98

Not necessarily. You could still be mosaic, or you might have a different kind of mutation that they didn't find. For example, we still do not understand the role of the information between the codons, but we have one person who has been identified as having the only flaw in her VHL gene between the codons, and a full-blown case of VHL.

It is true that it would be easier for them to find the mutation in your children if they had yours to go by. But they could also sequence the full gene just they way they are hunting on your own. So it's not impossible to check the DNA of your children, it's just harder (and more expensive) which is probably why they are resisting it. You are right to keep checking clinically. If anything should come up in one of the children that looks like it might be VHL, then I would insist on the DNA test for that child.

If they find the mutation in one or more of the children, and still can't find that same mutation in you, then it's for sure that you're mosaic.

Best wishes,
Joyce

karenga01

I know this may sem a bit off topick, but could this still be passed on to a child even if you had undergone preimplantation genetic testing? Could your child still end up with VHL? My husband and I are considering doing PIGT. That is the only way that I would be secure in the fact thatI would not pass this on to my children. Now I am begining to rethink this a bit.

inapeoplehouse

For instance,

In my case... I tested negative in 1997.. They say that was due to testing that was not the best, however...

When I was retested this past year, knowing full well that I had VHL prior to doing the testing... They were able to look alot closer and find mutation S65P, a change in amino acid at position 65 from srine to proline.... Without the fancy talk, it's basically just the tiniest little change in the gene... So tiny that they could possibly see it in someone not presenting VHL symptoms and overlook it... Even in me.. .they were, and are still hesitant to say it is exactly this tiny little blip that is causing my VHL as I (and my family prior to me) have such an aggressive strain of the disease.

This mutation they have identified, they have been able to identify in all three of my children and my mothers banked blood... so there is a slight possibility that it is just something that runs in the family that does not cause the VHL, however.... there is absolutely NOTHING else.. no deletion or changes that can be found in either my or my mothers blood... since my mother passed due to VHL related symptoms (as did her mother and brother and who knows whom else as our family stayed in the dark for many years)and I have presented with Hemangioblastomas in the Cerebral and 27 years old with RCC. We know that it is VHL so we go on the assumption that my mutation, which has only ever been noted on 4 people prior to me in history.... While tiny, is in fact, a hugely aggressive VHL change.

It's funny how it can all work out... again off topic and I appologize, but had to jump in here... EEK!!! :o)

Good luck to you in you testing with the further children... Let's hope that it was an unfortunate accident!

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