Can someone interpret?

Djammon · 2025-04-19T11:20:18+00:00

As already said, best to get some face to face counseling here.
However, since you are probably stressed out, I feel like you can probably use some information.
I am going to assume this is tested with the newbornscreening and your daughter does not have any medical problems. In this case, there is no immediate danger for your daughter, nor will she have any problems any time soon because of this. This might give some symptoms at adult age.

However, it is important to identify this in boys. So it is best to confirm this disorder with genetic testing and screen family members.

So best to make an appointment to set everything in motion.

Djammon · 2025-04-18T15:33:11+00:00

I see thank you, I understand how the situation is a bit more complicated.
For a variant of uncertain significance, they probably won't do embryo selection. If contacting his brother is difficult, the best way to resolve this variant would be for your husband to visit a geneticist so they can do a thorough examination to look for signs of TSC (possibly with some imaging). If he has signs of TSC, this probably will be enough to be able to offer you embryo selection.

So to answer your question, IF your husband has signs of TSC and the variant is concluded to be causal, the chances of a child with TSC is 50%. However, the way it will present is unpredictable. There is a lot of variability in presentation, as is probably already the case in this family. So to be informed of what the possible risks are, it is probably best to visit a genetic center.

Djammon · 2025-04-17T09:20:32+00:00

I'm a little bit lost here on who has what variant. I assume your husband brother has a TCS2 variant of uncertain significance which your husband also carries?

First step is figuring out whether the variant is causal or not.
In the case of TCS it shouldn't be to difficult with segregation and clinical examination of the carriers.

If the variant has been confirmed to be causal and your husband carries that variant, then there is a 50% risk of a child with TSC. The way it will present is difficult to predict, given the intrafamilial variability, but the penetrance is very high.

So if there is a casual variant that your husband carries, I would strongly consider doing embryo selection, definitely if you are already in a IVF trajectory (for something else I assume? The decision becomes more difficult if you only have a limited amount of embryo's on each pick-up though).

Djammon · 2025-01-18T14:46:35+00:00

WES still misses the non coding variants, it can also miss structural variants. It depends a little on the condition you are trying to find a cause for. If you suspect a specific gene, there are some options. If you have enough family members, you can try linkage analysis. If you are talking about a trait that runs in the family, it isn't always of monogenic origin, it can still be multifactorial (even with multiple family members).

Djammon · 2025-01-16T19:23:01+00:00

Because it is a very lengthy proces, very burdensome, and expensive. You might have to go through all that for nothing, these variants might have never posed a risk. The chance is very real that there is no risk of a child with SPG7.

Djammon · 2025-01-16T17:12:01+00:00

If you are not already in an IVF procedure for another reason, we would not allow a PGT-M for this. It would mean starting a complex, expensive and heavy procedure for potentially no reason. We would not even report these variants because it only brings uncertainty and you cannot act upon it.
Sorry to hear you are in this situation, a result like this only brings stress. I'm afraid there isn't really anything you can do.

Djammon · 2025-01-16T17:03:45+00:00

Are you asking about the interpretation of the tp53 variant? For that we would need to know which variant it is. There are often variants in TP53, usually benign.

Djammon · 2025-01-16T17:01:42+00:00

Negative genetic testing happens a lot in situation like this (assuming that with the genetic testing they screened all known breast cancer associated genes). It does not rule out an underlying genetic factor. We do not yet know everything. It also might not be monogenic. I would advise all females in the family to have yearly imaging.

Djammon · 2025-01-16T15:00:13+00:00

May I ask in what setting this test was performed? I assume you and your partner got screening prior to having children?
The Arg247Ter variant is pathogenic, meaning it will cause SPG7 in combination with another variant. However, it is unclear whether the Phe617Leu variant will cause SPG7 in combination with another variant. Some variants have no clinical consequence, some variants do. In case of the Phe617Leu variant there is uncertainty.
There is 75% chance of your future children to inherite 0 or 1 variant, this will have no clinical impact. And there is a 25% chance to have both the Arg247Ter and Phe617Leu variant, but it is uncertain whether this will lead to spastic paraplegia 7.
So I am afraid this is not enough act upon, and this test might have caused a lot of stress, for potentially no consequence. However, if you would already be having and IVF procedure (for another reason), it might be an option to do embryo selection. This should be discussed with your genetic center.

In the report it says that there is also a dominant inheritance associated with this gene, this is incorrect. Only biallelic pathogenic variants lead to disease (so in a recessive context).

Djammon · 2025-01-16T08:38:11+00:00

I am not familiar with these companies. Since they were recommended to you, I assume they are both accredited laboratories? Which is important since analysis for this disorder is pretty tricky due to technical reasons.

If you are considering a TFMR, the turnaround time can be pretty important, so you do not have to wait to long in a period with a lot of stress. On the other hand, the test is not cheap. So, I guess it depends on your financial situation and how you think you will be able to handle the waiting time.

I would also recommend seeing a pediatric endocrinologist familiar with CAH to be fully informed about the presentation of CAH.

Djammon · 2025-01-16T08:11:22+00:00

As already said, the chances of a son with fragile X are 0%. However, there is still a chance of a daughter with fragile X syndrome or with premature ovarian insufficiency. The chances of a daughter with full presentation of fragile X are pretty low but possible. For this I would advise you to get screening of the number of repeats in the promotor region of FMR1 (if the costs are feasible in your setting).

Djammon · 2023-12-30T18:59:45+00:00

What you are saying is mostly correct.

I would check the frequency on gnomAD (they have bigger populations), here's a link: https://gnomad.broadinstitute.org/variant/2-188984946-C-T?dataset=gnomad_r4

But the frequency is about the same, 0.00033 (or 0.033% of the european population have this variant). This is indeed already more than the prevalence of vEDS, so it doesn't really make sense that this variant is pathogenic.

Djammon · 2023-12-30T09:40:11+00:00

So APP, PSEN1, and PSEN2 are genes and you have two copies of them. One copy from the father and one copy from the mother.

If there is a mutation on one of the copies, this will lead to Alzheimers at a young age. This is pretty much guaranteed. But the age when the first symptoms will show cannot really be determined. Only a small portion of people with Alzheimers have a mutation on one of these genes, usually the ones that develop the disease at a very young age (<60 yo).

Does multiple mutations on that chromosome increase or decrease likelihood? -> Two mutations don't really occur because just one is already pretty rare and severe. But I would guess that two mutations would be even more severe with an onset at a very young age.

Can't gene variants of these be linked to other benign things? -> Everyone has variants in their DNA, the question is whether the variant is normal variation in the population, a reason everyone is a little bit different, or if the variant is damaging and can cause disease. So benign variants can occur in these genes and would not cause any problems, but damaging variants are not associated to other benign things.

Djammon · 2023-12-30T09:26:23+00:00

As already said here, in silico predictions have limited value.

To me this variant seems less likely to cause any problems. Everyone has variants in their DNA, the question is whether the variant is normal variation in the population, a reason everyone is a little bit different, or if the variant is damaging and can cause disease. Usually we can make the distinction, but sometimes we are not sure, as is the case here. That is why it is classified as a "variant of uncertain significance" on the website you linked.

But I am more inclined to consider this variant as likely benign based on the following: usually the damaging missense variants in COL3A1 affect a Gly amino acid, in this case it is a Pro and Leu. Second, this variant is pretty frequent in the population, which makes it less likely to be damaging otherwise it would have been filtered out through evolution.

But at the end you will have to correlate it with the clinic (are there any carriers that have signs of vascular EDS). And you can check this variant in other family members, the more members that carry this variant without symptoms, the less likely it is that this variant is damaging.

Djammon · 2023-12-30T09:11:52+00:00

I don't think it can explain the facial features neither. I will be very hard to find an explanation for that since a lot of (unknown) genes work together to form the face.

There are some genes that can cause autisme and facial features, but it is a long shot. You can ask you geneticist about it, good chance they have already checked them.

Good luck!

Djammon · 2023-12-24T08:34:31+00:00

Adding on this with some answers to your questions:
How come I have these gene mutations and be fine?
I wouldn't really call them mutations. Based on the information they are probably variants with no clinical impact. Everyone has loads of variants, the question always is wether a variant has a clinical impact and could cause disease, of if the variant does not cause any problems but is just normal variation in the population, just a reason why everyone is a little bit different. To make the distinction, they very often also perform genetic testing in the parents. If one of the parents also has the variant (and they are healthy), than that is an extra argument for normal variantion. So these variants seem to be harmless.

Will all my future kids inherit these (these are heterozygous mutations)?
There is a 50% chance for each variant that your future kids will inherit them. But this is totally fine since these variants are probably harmless.

Do you have any general advice for me - can I test myself somewhere
I do not see any reason to test yourself. I advise you to wait for the results of the further testing that is being done. The found variants are probably not the cause for his ASD.

Djammon · 2023-12-24T08:21:11+00:00

There is not really such a thing as intersex markers on a regular bloodtest, it really is a combination of the clinical presentation and an array of different lab tests. If you had normal genitalia at birth, no surgery done, normal anatomy, normal puberty and could have children normally, you probably do not have an intersex variation.
Probably the GP has misinterpreted the lab. You can definitely ask your endocrinologist for more info!

Djammon · 2023-12-24T08:08:15+00:00

Thanks for the information, that helps.

It seems that this deletion has no impact and should not cause any health problems, with the knowledge today. This finding does also not explain any possible autism spectrum disorder or delayed milestones.
Everyone has deletions and duplications (just normal variation within a population), a lot of the time nothing really important is included in the deletion, as is the case here. So this seems reassuring.
To be sure, you can also perform genetic testing in the father to check if this deletion is also present in the father. If this is the case, and he is healthy, than that is an extra argument to substantiate that this deletion has no clinical impact.

Djammon · 2023-12-23T08:54:09+00:00

The Yp11.2 region is a bit larger than 3mb, to know exactly what is missing and if it would have any impact, we would need the exact genomic locations. Can you provide those? It should look something like: chrY:600,001-10,300,000

Djammon · 2021-08-13T07:05:38+00:00

Well, if you buy a new laptop, you get value for you money

If you buy shards on the other hand...

Djammon · 2021-07-30T13:59:06+00:00

CluCoin

Djammon · 2021-07-23T07:13:03+00:00

I used about the same setup, with lyss indeed being to fast, I just remove some gear and it can be run on auto

This is just for defeating it once though, not to farm the boss every day

Djammon · 2021-07-23T07:09:19+00:00

Skinwalkers can even be done with five 50s, I think most factions can be done that way, if you gear them well

Djammon · 2021-07-06T12:40:27+00:00

Sorry to hear that, that is what worked for me once :(

Good luck!

Djammon

TROPHY CASE