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

Hi Merlot
I am sorry you are going through this. I am sending vibes from NZ {{{{{}}}}}}

I know very little about the technical stuff of chromosomal things etc but I wanted to tell you that a very good friend of mine here in NZ found out when her daughter was 5 and a half that she had a very rare chromosomal anomaly. Something to do with the 18th chromosome I believe.
She has been through a lot in the last 2 years getting to grips with her daughter's special needs and most importantly trying to get her head around her little girl's future (which is not the future she thought it would be when she was a babe in arms obviously ... I think that has been the hardest thing for her TBH ...)
I know that she goes to a website devoted to parents of children with rare genetic/chromosomal conditions and it has been a great help to here ... it is a UK based site as she has not found anything similar that is based in NZ. I can give her a ring and ask her for the address if you like.
G x

There is a group called 'UNIQUE' which supports parents with rare chromosome abnormalities - that may be the one?

Uniques website is www.rarechromo.org

I've just done a quick search and couldn't find any reports of duplication of the region of chr15 containing IGFR1 being seen in patients with autism..found 5 reports..all overgrowth, some mild facial features and developmental delay/mental retardation. If you are going to look make sure you are looking for the right region of chromosome 15 - there are lots of syndromes related to abnormalities of chr15 and most will not have any relation to your ds.

merlot - I have no idea about genetic info but just wanted to say - pleased you have some answers and sorry that things were missed BUT you made the best possible choice you could for you and your family with the information you were given.

Crap information in same parts and that must be frustrating.

It is hard for us as parents to come to terms with our children's diagnoses - even when we know in advance.... despite knowing - I still cried and cried and cried and then got angry and went through the whole gammit of emotions. Now it seems like I have never been without dd1 - can remember what it was like not to have her in my life and can't imagine life without her.

I can appreciate your feelings re the apology. Our dd1 ended up back in intensive care after her cardiac surgeries - once clearly even to a medically ignorant person like me - due to their mishandling and moving her whilst she had a chest drain in.... I challenged the head of PICU when he came to check dd1 out and to visit ICU and said to him I firmly believed and it was clearly evident that moving dd1 with a chest drain caused the fluid to build up and her to be back in ICU on a ventilator..... he could not look me in the eye whilst I was saying this and i know he agreed but there was no way we were getting an apology. Not even a verbal one. I just like you - wanted someone to say sorry - we stuffed up - and you are now having this worry again.....BUT nope.

I think you should write even it is to express your concern about the protocol ( if there is one) and to outline how it did not work in your case and how it might work better next time.... start with that.

Sorry this has turned into a ramble - just wanted to reply anyway from a parent point of view rather than a genetic pov iyswim.

Thanks everyone for all your comments - it is so good to have all your views. I havent got time to reply in detail right now, but will do later -we are off to the Zoo today (if it ever stops raining!!) so had better get ready.

Bluebear - just wanted to thank you briefly about the sperm-to-be explanation (very clearly explained and makes absolute sense, thankyou).

bluebear, you're right- I was too knackered to think properly last night and was thinking that paper must be referring to IGF2r, which is imprinted, and not IGF1r, which is the only one that matters here . I'm still kind of surprised that this was so hard to detect in terms of probes, it's megabases away from the telomere.

merlot, bluebear is right, the extra material can only have come from your dh. I think one thing that might conceivably be worth thinking about is how you would have felt if the CVS testing had been done properly. You would have known about the duplication, but because they are rare, and because there are probably no two individuals who have the exact same combination of genes duplicated, you would have been faced with a really hard decision. No-one would have been able to tell you the implications for health in any really useful form. You know what I mean, I hope, I'm not beginning to excuse the cack-handed way it was done, just thinking aloud.

Sorry Merlot - very genetic this bit! Especially for Tamum.

Tamum - I suspect that that the rec 15 had the dup material on it's p arm (in the satellites) - therefore on conventional cytogenetics it would look like a normal chr 15 but with maybe slightly larger satellite (which are a variable region as you know)...the dup would be invisible and unless the lab knew the breakpoints of the father's inversion there would be no impetus to FISH.
I was trying to check out what's in the MLPA mix last night but was too tired - it does seem unusual that a FISH test was not 'diagnostic' enough..but maybe they got more info on breakpoints or presence of IGF1R by using either MLPA or another molecular technique.

God - Bluebear and Tamum - you are very clever ladies

I'm glad you have answered Tamums question Bluebear. I was beginning to wonder whether ds2's anomaly should have shown up under standard resolution testing, but I can see from your explanation why it probably wouldnt have done.

Bluebear - Are there any technical questions which I could put to the geneticist which might help clarify things? I do know about the organisation Unique, but didnt want to `scare' myself unnecessarily by going on the site without knowing chapter and verse about ds2's chromosome change, so will do that a little further on down the line.

Reading the letter from the genetics department again, they say that whilst they know for sure that there is a duplication of the very tip of chromosome 15 they only suspect that IGf1R is duplicated and so they have taken some from dh and I to confirm this.

Can you throw any light on why they would know of the duplication of 15q but not know conclusively that IGF1R has been duplicated yet?

Fio - didnt realise that you are involved in a medical negligence case. How did you get the ball rolling with that?

merlot at least you have the dx you craved, even though it might be not what you wanted.
I like fio have medical negligence suit going on but my ds2 has no dx and his probs are not genetic.
I can understand your anger etc.

Sorry to here that you too are involved in a medical negligence case

Thanks Fio Good Luck with your case.

can I carry on fio

sorry doormat...also meant to say..that yes..having a diagnosis is making things easier in so much as I can concentrate my energy in the right direction not so much on ifs whats and maybe's iykwim. Hope you get a diagnosis soon.

merlot carrying on from fio
they will dig out all your records and your childs.
A neo-natal specialist will look into your childs records to see if there is a case
A gynae will check your records to see if there is a case.
These are done independantly and of eachother. Reports will then be sent to see if there was negligence involved.
TBH Merlot I dont think there will ever be a dx and I dont think it was natural neither.But I love him to bits for who he is and enjoy everyday I have with him

And if you have a dx it can help with getting help in schools, if things like statements are needed. Much easier to get IME if there is a specific dx.

This is wrong, the child's needs should be ther determining factor, but it is the case in my experience

tbh mb it didnt matter about dx for my ds2, he was statemented at 3
but can understand why a dx will help for other kids so can get proper education and help.

Oh agreed. But sometimes it can help to speed things up a bit, for some kids.

Merlot, I am very impressed if you followed my post to Tamum..you have been doing a lot of research!

If I put myself in your shoes, meeting the geneticist again, I would write to them first and request that they ask the lab for photos of your dh's and ds's chromosome 15s...I know that you won't be used to looking at chromosomes but it may help for you to see them to understand, firstly how the duplication happened and secondly how it couldn't be seen easily..(chromosome analysis is carried out by people looking at the chromosomes, haven't invented a machine yet as good as the human eye/brain) You would need to request it before your meeting so they could arrange the pictures - labs don't routinely send pictures to the doctors. I have 'sat in' on counselling sessions and the docs are good at using pictures to explain, but I think a photo may help..especially since chromosome 15's have regions which are variable between everyone.
I would also ask them about other 'segregants' that are possible - these are the other ways that your dh's inverted chromsome can give rise to abnormal chromosome - there will be at least 1 other type of abnormal chromsome that can form which would be a deletion of the same region of the chromosome that your ds has got duplicated..the other type will give different features (e.g. short rather than overgrowth) - this is to give you information in case you do decide to have another child or if ds is a carrier and you need to support him.
It may be irrelevant to your ds2 but I would prefer to have as much info about your family's inversion as possible.
I can't think of any 'technical' stuff that would help...

Do you mind me asking..how did you find out that dh carried an inversion?

For your other question - duplication of material from the long arm of chr15 can be confirmed by a simple FISH test (would be interested to know why it was more complicated for your case)- the fact that your son is tall infers the involvement of IGF1R but there is no standard test for IGF1R available to the routine diagnostic chromosome lab...to see if it is actually involved they would either need to send it for studies at the National centre (which may have a FISH probe, or may make one especially for them), or carry out DNA studies of the region - which may also need a research lab.

Hope this helps.

I mean if I were you I would want as much info about my family as possible...

I am reading between the lines a bit Merlot - in my post to Tamum I described the 'most likely' rec 15 in my experience - please bear in mind that I don't know enough about your dh's inversion to know that it is the case.

Yes of course Bluebear - I realise that you are only surmising and will remember that.

We found out that DH carries an inversion because DH is also subfertile. We managed to have Ds1 naturally (after a year of trying) and then when we hadnt managed to conceive another child by the time ds1 was 3 we considered IVF. During initial screening for IVF, DH had a genetic test which detected the translocation. After consulting a geneticist we decided (of our own volition) not to proceed with IVF because of the agonies of IVF and then to be faced with the possibility of termination on the grounds of chromosomal abnormalities. We did decide, however, to let nature take its course though because we were reassured by the Geneticist that a CVS test would identify any abnormality resulting from my DH's inversion (this is obviously not the case however!!)

Thanks for the advice re-the asking for photos etc. DH's sister was tested today and his parents have now agreed to be tested too, so we will obviously have a much better picture there as well.

An awful thought has also just occurred to me - when we saw the original geneticist back in 2000, we were consulting him because of the test results from the IVF clinic. I know he would have had a letter which referred us to him, telling him that DH carried a balanced pericentric inversion of chromosome 15 - but I now wonder if he actually had the complete lab details. Of course, DH and I wouldnt have known then whether that was important or not - we naively thought a balanced pericentric inversion of chromosome 15 was a definitive description of DH's anomaly and that was it. Where it obviously now transpires that there is much, much more to it than that (that description alone could probably relate to hundreds of people with translocations I guess??)

If he hadnt had the full lab details - surely he couldnt have done a proper job of counselling us? Surely it was negligent to just write to the GP and suggest a CVS test for me without having any real detail on DH's translocation. The more I think about this, the more it stinks quite frankly.

Thanks bluebear, I can see that if it's like that it would complicate things. I'm still grappling with all these bits of information though. Merlot, I think in all honesty you need a good paper trail- what was in all the letters. I would be horrified to think any geneticist might consider all inversions as being roughly the same and not need more information on the precise details, but I'm beginning to wonder what was going on.