Calling Tamum and all other mumsnet geneticists please - looks like we finally have a dx and I need some help please.

[merlot]

Hi everyone,

Well it looks like we finally have a dx for ds2.
I feel relieved that the search' is over but also saddened that we now know there is something physical causing ds2's special needs. Another complication is that I am troubled by the quality of antenatal counselling we received and would be very grateful for your views on this. I need to understand things more clearly before I can reach any degree of closure' iykwim.

Some of you will remember that my DH carries an inversion of chromsome 15 and as a result when I was pregnant with ds2 in 2002 I had a CVS test which was ordered by my GP on the strength of a letter written to her in 2000 from a geneticist who had advised that because of dh's inversion we should have a CVS test to identify any genetic abnormalities.

The CVS test was carried out at Kings College Hospital by Prof Nikolaides and I was rung up by a nurse 2 weeks later to be told that all was well and that my CVS had tested negative to genetic abnormalities. Are you sure? I asked and she replied yes. However, she said that there was a statement on the results which said Under Standard Resolution testing Chromsome 15 looked normal, but we do not have details of the father's rearrangement'. I asked her what this meant and she said that she didnt know but would send me a copy of the report. I, in turn, asked my GP what the statement meant and she replied that she didnt know, but that fine meant fine' and that I shouldnt worry about it.

Ds2 was born and it was clear to me fairly soon after birth (6 weeks) that things were not right and he didnt seem as responsive as his elder brother had. It also became clear that ds2 has only one kidney, something that had been dx antenatally as hydronephrosis.

We then began a round of investigations and consultations with a developmental paediatrician who ordered some genetic tests which turned out to be fine again.

Sorry for all this rambling...but I am nearly there now...

Anyhow we have just discovered that Matthew does in fact have a genetic anomaly, but that it would never have been detected by standard resolution testing: He has a 15q sub-telomeric duplication, which is entirely consistent with the fact that ds2 is so tall (because a duplication leads to an extra copy of a gene called IGF1R which has growth factor and can result in overgrowth)

Apparantly 15q duplications are uncommon and therefore we still do not know much more about what this means for ds2.

My unanswered questions are these:-

1. What do you think of the quality of the geneticists advice in 2000? He made it sound to us (and obviously the GP) that a CVS would identify any genetic abnormalities - which was clearly not the case. Was this sound advice in 2000 given the info they had then. Was it known that CVS might not detect minor alterations in genetic makeup? Was there any other sort of tests available to us antenatally that would have examined the telomeres?

2. What do you think about the GP ordering the CVS without reconsulting the geneticist. It strikes me that with the leaps and bounds that are being made in research in this area it was rather foolish (??) to order genetic tests without reconsulting the geneticist again to make sure that this advice was still relevant. I did, in fact, ask the GP whether we should see the geneticist again when I fell pregnant in 2002 and she was quite clear that there was no need. `It says here that a CVS is what needs to be done...' etc..

3. Whose job was it to pick up on the statement in the genetic report copied to my GP and myself from Kings College re-the we do not have details of the father's rearrangement?

4. If Kings had been given details of the father's rearrangement in Feb 2002 what tests would they have done?

5. Finally, where the heck do I go from here.... I love my ds2 completely and utterly and know that my sons special needs are what make him, him. It would not be possible for my son to be here without his special needs - I accept that. However, I cannot help but think what life might have been like for the rest of us...had we been given all possible choices and more significantly if the advice had been different in 2000, I could have chosen not to conceive at all. I also am keen that lessons should be learned from this and that the best possible advice should be given to others who might find themselves in our position.

If you have got to the bottom of this post - thankyou. I really would appreciate your help and views

I can't help, merlot - sorry - tamum was around earlier. I will bump this for you tomorrow if you haven't had any replies.

OK a bit out of date, but I would say:

1. It would certainly have been known that a CVS could not pick up every eventuality. A lot of things can only be picked up if they are specifically tested for, without testing for them they won't be picked up. If you were told that OK CVS meant 100% OK baby then you were mislead.

2. POssibly wouldn't have made any difference.As your sons' rearrangement is different I doubt it would have been picked up anyway- the CVS would have checked for obvious abnormalities (such as an inversion) but that's all.

3. Here I think the onus was on the GP to find out what your dh's rerrangement is and had that been checked for (it may have been?) Really I guess this should have been forwarded along with the CVS sample, but as that was missed, then the GP could have picked it up. whether they :"should" have is a slightly different, but I would say if they were being thorough that should have happened. However as the rearrangement is different from your dh;s that may not have made a difference anyway. Did the GP know your dh;s rearrangement? If they did then I think its fair enough to say fine is fine (as an inverison should, I think be picked up on CVS), if they didn;t know its a bit dodgier.

4)They would just have looked for an inversion (which is prob why the CVS was suggested by the genetecist). An inversion can be farily easy to spot, a duplication is harder- and may require more specific tests. It depends on how big each of these rearrangements are though.

5). I think - from the little you have posted that it sounds as if it is just "one of those things" and a piece of crap that life has thrown at you, unfortunately (and your son of course). It sounds as if your son;s chromosome abnormalities are unrelated to your dh's (although again just going on what has been said, there could be specific cases where that;s not true).

Hopefully Tamum will be along soon, she knows far more about this sort of stuff than me.

Hi Jimjams

Thanks so much for replying.

I probably didnt make it clear, but we have been told by the overgrowth specialist that dh's rearrangement is indisputably linked to ds' telomeric duplication - apparently dh's inversion goes right into the tip of chromosome 15 and whilst the rest of the chromosome in ds2 has managed to align correctly the tip (the telomere) didnt.

You are right in that dh's inversion is so large that I think they expected to pick up any change in ds2's genetic material under normal CVS.

The GP didnt have details of DH's inversion, but she could have got them had she contacted the original geneticist.

Oh right, that puts a slightly different gloss on it. I suspect the technicalities are outside the remit of a GP. Unfortunately they may be so outside the remit that she may not have realised that it was a possibility iyswim. I think had I been in her position then I would have wanted to check with the genetecist to cover myself iyswim, but I suspect I know slightly more about cytogenetics than her and so am more able to recognise my limitations.

Gosh its a difficult one. How would you want to take it further? IN your situation I may reel of some sort of letter, I would personally be cautious about going for compensation because I would be concerned about the added stress that would give. However if your chances of winning are high (I have no idea whether they would be or not), and any compensation could benefit your son then I would consider it.Unless my chances were very good I would drop it though as I think our lives are stressfull enough as it is.
How does dh feel about it?

Oh god, what a mess. I'll just try and answer briefly and then have a think.

1. Crap. They should have picked this up, it was obvious it could have led to this. My guess is it's a small duplication, but that's no excuse when they knew your dh's inversion. They shouldn't have been doing standard karyotyping, and should have had precise details of your dh's inversion. They could have picked it up by FISH.
2. Yes, in an ideal world the GP should have consulted the geneticist, but this kind of duplication would have been detectable in 2000 too.
3. I don't know, sorry.
4. I think FISH- there are other dosage assays available now but not routine diagnostic ones, I don't think.
5. I will have to think. You need bluebear really, she works in a diagnostic lab.

Oh merlot, I'm so sorry.

Just thought- are they going to test your SIL?

I dont really think I am after compensation...more a case of recognition that more should have been done and that it was almost a `catalogue of errors' perhaps that could have been avoided if there were certain protocol in place. Things like...only geneticists should order CVS' that are to ascertain unusual genetic conditions and maybe that Kings should have overtly and not obtusely asked for details of dh's rearrangement.

Saying that though, I feel sure that if we were told that there was a high chance of compensation which would provide for any long term care for ds2 and would make life easier for ds1 who will undoubtedly be limited by ds2's special needs - I would have to say I would probably go for it.

Interestingly DH has not mentioned too much on the subject. He was absolutely adamant that we should have a termination if Ds2's CVS had come back positive, but since DS2 has arrived he loves him so much that I suspect he feels he would be `wishing him away' by pursuing this too vigorously.

I can see what you are after, but in the defensive medical negligence culture I'm not sure you would get it. Oh its hard. xxxx

It does seem that your GP has just ordered a standard karyotype without thinking it through. My guess, and I may be doing him/her an injustice, is that they just thought in terms of the inversion as opposed to the result(s) of an inversion.

Thanks Tamum - I really appreciate your advice, as always

Do you know your post made me cry. Jimjams asked me what I want most from pursuing this..and I've just realised what it is...its a bloody apology and for someone to say what you said. `What a bloody mess....we are so sorry'

When the telomeric stuff was being explained to us - I remembered something that you had written to me in an email. The larger the parents change, the smaller the offsprings change is likely to be. Apparently it is a very small duplication, so this really is a case of that isnt it? Do you think this is even more reason why they should have examined the telomeres?

Unfortunately because of the excess growth factor, ds2 is also more at risk of Wilms tumours so he now has to have a scan of the kidney every three months because he only has one kidney and a tumour would obviously be very bad news

I am not really shocked that Prof Patten (named names now - so fed up with the man) should have picked up on this - as soon as it was explained to us by Prof Rahman that dh's inversion went right up into the tip, I understood what Kings had meant by that statement

Maybe I need to consult the GP on this - think she will be very shocked if she finds out that more than a standard CVS should have been recommended.

Look forward to hearing more from you in due course. I really do appreciate the time you have spent on this - from start to finish - for me.

Sorry to keep coming back to this- I don't know that we know how bad the geneticist's advice was in 2000 actually. It may have been fine, because he may not have specified routine karyotyping. I think that the GP was at fault, but I honestly don't know how good your chances of any claim would be. Trying to be dispassionate about it I would say it was certainly not thorough, but it was more a catalogue of minor mistakes leading to a very big one than real negligence. Maybe Countess Dracula could help though- I think her dh deals with medical negligence cases.

Hi, as Tamum said I work in a diagnostic lab - in subtelomeric screening as it happens - would you like to CAT me.
BB.

yes will do BB - many thanks

Oh merlot, I cross posted. I am sorry I made you cry. I just know how utterly frustrating this must be, and in a way it's harder because it's so difficult to pinpoint where it went wrong. You're right of course, that the duplication size is probably tiny because of the large inversion, but I still think that if it spans the IGF1R gene it can't have been that hard to detect- the really difficult subtelomeric rearrangements are the tiny little ones away from any genes. There would have been probes available in 2000 for sure.

Oh crap crap crap. I want to swear profusely on your behalf but had better not. I know this sounds ridiculous but I guess it is good that they know now and can scan his kidney- Wilm's has a really good cure rate when it is caught early.

Bluebear, the cavalry- thank god for that

Yes, I thought that too about the Wilms tumour.

Have to say that I feel we are in really good, safe hands with Prof Nazneen Rahman. She seems amazing and really switched on

She said that Wilms tumours are very treatable too and that by scanning as frequently as this would give a good chance of whipping out any affected area as soon as poss. Apparently he would no longer be at risk after the age of 5.

Sorry, I also forgot to add that both Dh's sister and parents are now being tested as they do think her difficulties are likely to be related. You know..it is a strange thing to say, but I almost feel vindicated on this whole matter. It is so logical and plausible that ds2's difficulties are linked to the 15th that it now actually makes sense and that makes me feel so much better in a strange sort of way.

Just want to say briefly that the subtelomeric probes (developed by J Flint) weren't really on the market in 2000 (I had access to them but we were trialing them for the manufacturer) - so I would not expect FISH to be mentioned in your 2000 letter.
They were available in 2002 though.
The biggest error I can see is that the lab obviously weren't given details of your husband's inversion (hence the comment on the CVS report) - the scientists in the lab know how inversions can result in recombinant chromosomes which have duplication/deletion of genetic material..but they need to know certain info about the inversion so they can work out what the recombinants will look like and therefore how (or if) they can detect them.
If we get poor clinical info (eg. 'father has abnormality of chr15' rather than 'father has inv(15(p11.2q26')) then we contact the clinicians and keep nagging them until we get a copy of the parent's report (we get them faxed from all over the world) - and if we can't track one down then we suggest we get a blood sample from the parent so we can test it ourselves and compare it to the fetal karyotype - but we still get clinicians ignoring our calls and requests so occasionally we have to put the disclaimer into the report to try to spur them into action.

oh and Tamum is right - FISH is still the test used for subtelomeric rearrangements - our lab is trialling a new method (microarray CGH) but for a known familial rearrangement FISH would still be used.

Please CAT me if you want more info.

Knowledge can bring some peace I think. I know why you want an apology and can completely understand it, but I think you are unlikely to get it. Hospitals are too defensive.

I think having a talk with the GP and a genetecist is a really good idea- a chance to get your questions answered- and you may get an apology from an individual as well (unless their unions tell them never to apologise).

I'm pleased you have a good prof now. Must make things a little easier. (small comfort i know)

I can see exactly what you mean- it seems so unlikely that all these things should have been unlinked. It will be interesting to see which of your parents in law have the inversion, because the extent of any similarity between your SIL and Matthew could well depend on whether she got the inversion (assuming she has it) from her father, which would be the same in terms of imprinting, or her mother. There's a report in the literature of autism caused by 15q duplication only being associated with maternal transmission, which of course hasn't happened with your ds, but could have with your SIL.

Merlot, I'm going to bed now but will check on this again in the morning. I know bluebear will be able to help much more because what you can do in the lab, and what is actually practicable in a diagnostic setting are really quite different things.

Goodnight x

BB - I have CAT you already, but I dont think there is much more to ask at this point in time - but can I come back to you if I need to?

I have become something of a mini expert on all this testing stuff , so I actually asked Prof Rahman whether the Fish stuff had shown the change and she said that it hadnt been very clear under FISH and that they had applied some very recent technology to it to be conclusive...wonder if was the new stuff you are testing?

Not exactly the same, Merlot, but I had a bit of a battle with CVS with the same team at Kings'.

DD1 has a known genetic disorder, with a huge range of possible variants so we needed to know the variant to get CVS reliably. She also has a brain abnormality which at the time they had no diagnosis for. We had CVS for dd2 at the last possible moment (I didn't know I was pg till quite late on as DD1 was in hospital and I had enough on my plate). It was a huge fight with various labs to get data for DD1's variant and to get the confirming DNA tests done for us as parents. There was a lot of correspondance from the geneticist who was very efficient, but when I turned up at Kings' they had no record of who I was or what they were testing for. They were only going to take one sample (we needed 3) and I had a huge fight to get them to contact the geneticist to confirm this (I refused to do the test till they cleared this up) and even then had to confirm and reconfirm even as they were doing the procedure.

Bit of a waffle but - part of my point being that most of the onus to get this done correctly was on me. Which stinks, frankly. The other part being that I was sent to Kings' by my local hospital not because they thought it was the best place, but rather to save money as their charitable status makes it much cheaper for the NHS trust than doing it locally. The downside is that they have huge throughput and you lose a lot of communication you might have if everything is done by one team of people who talk on the phone regularly.

Goodnight Tamum

Yes, I googled something tonight about a link with Autism.

Prof Rahman has taken blood from me and blood from dh to ascertain where he has got the extra bits and pieces from.

This is how I understood it...but could have got this wrong...DH's balanced inversion makes it difficult for genetic material to line up properly during reproduction - so there is a chance that our offspring are at risk from gaining extra material (like ds2) or deletions. I thought, however, that it would equally possible for ds2 to have gained that extra material from me as from dh - am I wrong on that??

If ds2 could have got the extra material from me, does that mean he could be autistic?

Its just that I do see quite a lot of autistic traits in him - not least the lack of speech and communication. However, I am also aware that there are often autistic overtones in a whole host of different syndromes.

r3dh3d - thanks for this. I do see exactly where you are coming from.

You are right. I remember Prof K asking whether we had details of dh's chromosome inversion and we just parroted out that dh has a balanced pericentric inversion of chromosome 15 - but of course, we didnt know or understand anything more at that time. It all comes clearly into focus now though

From what you say, it would appear that they should have had details of the inversion BEFORE they even did the test then. Very Interesting. Thanks so much.

Tamum the maternal inherited dup(15) is of region 15q11.2 (same region as PWS and AS) - 15qter not imprinted as far as I am aware.

Merlot - there is a dosage test called MLPA which is 'rolling out' to labs at the moment - this can be used to look at telomeric regions too and is most likely to be the 'new technology' mentioned. .
...the new technology we have is enormously expensive but can test all of the most likely parts of the genome that are likely to have abnormalities all in one go - subtelomeric regions are included but also lots of other syndromes..when it's more widely available, hopefully it will cut down on the long trial and error testing that families have to go through at the moment.

The 'lining up' of the chromosomes happens in the sperm cells (or egg cells) when they are being formed..so the misalignment would have happened in one of your dh's sperm-to-be cells - the resulting sperm would have the recombinant chromosome 15 (with the duplication).
That sperm went on to fuse with your egg (which would have had a normal chromosome..so the extra material would have come from your dh.

As others have said, I think it would be a really good idea to talk this through with a geneticist (in my region this would have been recommended with the report)