Genetics FAQ

Could an individual have more than one duplication?
We have one son who was PTN11 Noonan Syndrome and another son who has a clinical diagnosis. Last year the son with the clinical diagnosis was retested for Noonan Syndrome and was found to have a chromosome sex duplication. Should we have our other son retested? Is it possible for a Noonan’s child to carry another duplication? This is a possibility as just because you have a particular gene test result for Noonan Syndrome doesn’t mean there wouldn’t be other things. That can sound worrying but actually differences in genetic material are really common and if we look closely enough we’ve all got them. Larger differences that can have an effect are a bit less common but it would be wise to get it checked out.  Question asked and answered at our family’s day 2015
Do we know of any medical problems that arise in adulthood with Noonan’s?

My son’s eight and we’ve identified everything he has an issue with medically. I was wondering if any other medical problems can arise with Noonan’s later on in childhood or into adulthood, other than maybe delayed puberty.

A lot of these syndromes are described in childhood and we get most of the information in childhood but what we want to do is follow it through so we have answers to that question. As a general rule most of the things that we predict in childhood are carried through but we don’t see other things developing. But in some cases, lymphoedema has developed in adult life, which we didn’t predict, so I think we need to do further studies to answer that in the longer term.

Question asked and answered at our family’s day 2018

Do we know when the mutation occurs?

When it doesn’t run in a family, is there any understanding of when the mutation occurs? Is it always pre-fertilisation or is there evidence that it can happen during development and then you get mosaicism?

Mosaicism has been recorded for RAS-MAPK pathway disorders but it is thought to be exceptionally rare, and where there is an enrichment for the spontaneous mutation is in the spermatogenesis where sperm are turning over all the time, there’s lots of cell division, there’s lots of DNA copying that needs to happen and therefore there’s a much greater chance that it happens in the sperm generation as opposed to the eggs that just sit there and don’t have to do lots of dividing. So, the evidence is that over 90% of new mutations will be of sperm origin. There are also emerging studies on older fathers whose sperm generating cells have had more cell divisions having a higher chance in actuarial terms, going from one in an extremely large number to one in a slightly less extremely large number as the decades pass. There is a study that’s just staring in Oxford looking at the origin of mutations which might be relevant in the future to understand that further.

Question asked and answered at our family’s day 2018

How will the 3D study benefit my family?

We’ve got three kids, all grown up now but we also have a grandson who’s been diagnosed with Noonans. “J”, my youngest daughter, is one of the 30% for whom they don’t know what caused the Noonans but our grandson who is J’s nephew, he’s under the 3D scheme which I think is being run by Cambridge University and the geneticist at Middlesbrough who saw J is waiting for the results of the 3D study to see whether there’s any links. How do we make sure all these studies are linked together and the results are correlated and we get the best benefit out of them?

The 3D Study was set up to look at 12,000 children that was later extended to adults across the UK who display intellectual disability. Enrolment has been really through genetic services. The study only stopped recruiting in April 2015 and it was a actually a much bigger task than people thought it was going to be to just deal with the sheer volume of samples in terms of new technology so the first few years – it lasted 5 years – were actually very much about getting the actual experimental processes to work. And we really only started to get a lot of results in the last 12 months. As part of that process, people can express an interest in research into particular genes and our intention is to take forward the rasopathy genes and to look at those patients who were identified through the 3D study as having one rasopathy disorder which would most commonly be Noonan Syndrome to see what we can learn because they would presumably be people who are less typical. We’ve already seen some people in Manchester through 3D and other studies who have been found to have Noonan Syndrome 

 Question asked and answered at our family’s day 2016

Is it possible to have more than one mutation on the RAS pathway?

Have you found patients with more than one mutation on the RAS pathway?

Yes. But sometimes we only look for one gene like PTPN11; we weren’t systematically looking at all but now we run a panel of maybe 10 or 12 genes and we occasionally find one that’s got more than one gene fault. It is possible for example to have a child with both the Noonan gene and another genetic condition causing short stature. It’s going to happen by chance occasionally but probably relatively rarely but with increasingly accurate testing, there will be more identified. It does seem to be a chance event rather than any biological principle underlying it.

Question asked and answered at our family’s day 2016

Is it sensible to re test for the genes if unknown?

If a child was tested in the past when they couldn’t identify the gene, should she be retested and if so, if the child isn’t seeing a paediatrician, should this be arranged through the GP or straight to the genetic centre? 

The number of genes identified keeps increasing so if tests were done some years ago it could be more specific results from a new test would be helpful. Paediatricians should be able to do the tests but, in this case,, the approach should be through her GP because that was the usual way it was organised in the Health Service and the GP can make a direct referral. To the regional genetic centres.

Question asked and answered at our family’s day 2015

What is the difference between CFC and Noonan’s?

My daughter’s mutation is MAP2k1. Quite often, when I see pictures of the pathway, that only comes under CFC Syndrome and Noonan’s isn’t mentioned on that mutation – I just wondered why?

There is a definite overlap between Noonan Syndrome and CFC Syndrome and where the lines are drawn is not clear at all. Often, it’s relatively historical about in which group of patients the gene changes were identified first, and so for MAP2k1, that was one of the original genes described as being a cause of CFC Syndrome and that then got its label as a CFC gene. As testing has been extended, there are more and more people with what looks clinically like a Noonan Syndrome phenotype who pop up as having a change in a previously CFC described gene. There has always been a few people known to have MAP2k1 gene changes in a fairly mild phenotype and they are in the literature here and there, and this degree of overlap is sufficient such that the way some labs now report their testing is “This result is consistent with a Rasopathy” which is fine as long as all of you guys who have Noonan Syndrome as part of your family know that Noonan Syndrome is the archetypical Rasopathy. We’ve had issues where paediatricians have sent for genetic testing and the result says “consistent with a Rasopathy” but the paediatrician nor the family have never heard of a Rasopathy and things become very difficult until we’ve been able to catch up with them and explain that it all makes sense. So, there are people with mild patterns of difference who have MAP2k1 mutations that were more characteristically described in people with a more severe CFC phenotype. The dilemma is do you define diagnosis by the gene or do you define it by the clinical features? I think probably we’re defining it by the clinical features first and then looking at the gene, but it’s an ongoing discussion. The best known and most widely used diagnostic criteria for Noonan Syndrome were done nearly 20 years ago before we had much gene testing at all. At the meeting in Milan we’re having a session on what should be the diagnostic criteria for Noonan Syndrome. Originally it was about the face, your stature, and whether or not you had congenital heart disease or a relative affected. I think they’ll be very different now and they will somehow have to incorporate a gene change.

Question asked and answered at our family’s day 2018

What is the future for genetics?

This is a question on the future of genetics. With the advent of cell and gene therapies that’s started to emerge – we see more and more about on the media – is there any prospect for genetic disorders to be treated per se rather than treatments being focused on the ailments that result from the syndromes themselves?

 I think that there is some interest in whether certain classes of mutation might be amenable to treatments that might modify the expression of the abnormal gene, but I think we really are a long way from gene-based therapy in developmental disorders because the diagnosis isn’t made until many of the manifestations are present so I think in the short term we are looking at treatments that might be directed at manifestations of the condition.  I spoke to a professor who was interested in gene therapy and he looked into Noonan’s and because it’s very heterogeneous and he’s not completely understanding what the proteins are doing so he’s not really sure what kind of gene therapies are doing and he’s also – if you look at NS it’s not really deadly – it’s not that severe so they’re first of all looking for gene therapies that are very deadly at a young age so probably it will be in the future but as I understand now at the moment it is not a focus of interest. 

One possible exception is the Novartis Study which is looking at targeting in particular proteins within the pathway and I think it’s still very early days but it’s possible for these sorts of drugs might potentially halt the progression of the thickening of the muscle in the heart and potentially in some cases may even reverse it. There’s animal data on this and some anecdotal reports of these drugs being used in children with disorders of the RAS pathway so it’s possible there might be some progress – it’s not gene therapy as such but it’s gene guided therapy that might improve some of the features we see in the heart but I think we’re still some way from this being seen as a routine treatment.

Because this is a pathway which is so important in cancer – this pathway was first recognised in 1982 and there’s been tremendous work done on modifiers of this pathway but the difficulties when you realise changes in this gene causes developmental disorders is that the side effect profile of what you would accept with someone with cancer is completely different to the side effect profile of someone – a child – with developmental disorder. We’re still very much at the stage of understanding the inter-relationships of the pathway and there’s a lot to be learned about just how it functions in the cell normally but then of course you have on top of that, mutational genes but people are very positive about this group of disorders that there will be treatments and the work that’s going on is directed at that but it’s just that it’s going to take some time. 

Question asked and answered at our family’s day 2016

What research and support is there for adults with Noonan’s syndrome?

What research is going on for adults aged over 30 with Noonan Syndrome, and where can they get help and advice?

A study with a cohort of families started in 1985 and most of them are now young adults in their twenties. Hopefully the group can continue to be followed up so that we’ll really know what’s happening later in life. There was also a collaborative effort across Europe to try to understand the natural history of the cardiac complications of Noonan Syndrome. Also, clinically, there are a number of specialised centres for example cardiomyopathy expert centres in the UK, which have a lot of experience of looking after adults with Noonan Syndrome-related congenital heart disease. It is important to remember however that Noonan Syndrome was not progressive. There could be complications later in life but many people remain in good health with no further problems.

Question asked and answered at our family’s day 2015

Will doctors screen embryo’s for Noonan’s?

How open are doctors now to screening embryos for something like Noonans?

This is very much a question of personal choice. The GP can talk through the options with the person. The normal test is 9 or 10 weeks into pregnancy but even though it can indicate the gene is there it can’t always tell how severe the Noonan’s is going to be, and even in multi-generational cases, there may be differences between one generation and another.  This needs to discussed sympathetically by the GP with the person in question.

Question asked and answered at our family’s day 2015