A personal view of genetic diagnosis using modern DNA sequencing technologies

One of my research area is the diagnosis of rare genetic conditions and in that context I collaborate with David Kelsell at Queen Mary University of London. One of the interesting cases we have analysed recently is an extremely rare condition in which the patients suffer severe chronic skin and bowel inflammation. I was in charge of the analysis of the sequence data, so for readers interested in the technical aspects here is a short overview: this was a sequencing project of pooled DNA (from three samples, only one of them relevant to this study), using a capture array to enrich for regions of the genome showing evidence of being linked to the disease. I first came across a 4 bp deletion in the ADAM17 gene, and it was rapidly identified by David Kelsell and his team as a likely cause of the disorder. Further functional work confirmed that this variant is almost certainly the disease-causing mutation.

This study was published last year and an interesting aspect is that the individual in whom this mutation was first seen is now 19 years old, doing well, and entering his second year at the University of Cambridge. Daniel MacArthur and myself met with him to discuss his thoughts and feelings about the whole experience.
First of all thank you very much for taking the time to talk to us at Genomes Unzipped. Before we start can you tell us how your general health is? Do you want to describe in broad terms what your genetic disease implies?
My health is OK overall but quite cyclical, which it typical for dermatological conditions. It is overall very manageable using a combination of anti-inflammatory steroids and antibiotics. It has been much worse in the past and I am now in a rather steady state.

As far as you can tell, when did the effort to diagnose your condition start? And in which place and with what tools?
As far as I remember really, it started at least when I was 3 or 4 yrs old but probably earlier. I was treated at the time at St Mary’s hospital and I remember a doctor telling us there that 2 weeks should be all they need to diagnose the problem. Obviously it turened out to be more complicated than this. When I was 6 I started being treated at Great Ormond Street Hospital (GOSH), the main children’s hospital in London. I went there regularly for many years.

How many diagnoses do you think you have received over the years? What doctors have you mostly been interacting with?
Yes quite a few diagnostics were suggested indeed. My doctor at GOSH was John Harper and he has kept looking after me for many years. He initially thought I had some version of Netherton syndrome, which turned out not to be the case. I went through quite a bit of genetic testing though using the tools available at the time, which obviously were not the same as today. Another diagnosis suggested at the time was trichotyodystrophy. As for Netherton syndome one of the clues that pointed to these conditions is a specific hair defect that is associated with my condition. The other doctors I have seen after that were Dr Edel Ann O’Toole and more recently Prof Gideon Lack and Prof David Kelsell (who is the senior author on the New England Journal of Medicine paper).

As of today, does the near certain knowledge of what your causal mutation is has implications for your health?
In fact yes. The first thing is that before the diagnosis was made I started an anti-TNFalpha treatment which was essentially pointless because my TNF-alpha production is very much limited by this homozygous loss-of-function ADAM17 variant. So this stopped this (expensive) treatment at least.

The identification of the causal variant and gene also suggested a new drug called Alitretinoin, a retinoic acid that is meant to increase the expression of other genes in the same pathway, in particular ADAM10, which can hopefully compensate for my lack of ADAM17. I started recently but so far it seems to help. Perhaps too early to be sure however.

Even in the absence of obvious practical implications, does that knowledge seem beneficial to you in any way?
Very much so. Knowing what is going on, being able to get some understanding of the problem is a big relief. Knowing that the trait is recessive and that I cannot pass it to my children is also great news.

How did your parents feel about getting this diagnosis?
They were very happy about it, especially my mother who has been incredibly committed to figuring out what is going on. She was really pleased about getting, at last, a convincing diagnosis. This has taken so many years and so much effort…

Can you tell us about your general experience with the UK NHS? Do you think you receive a particularly high level of attention? And if so, why?
I like the NHS, and they really gave me state of the art care throughout the entire process. Technology was not there to enable diagnosis but as soon as sequencing became available I could take advantage of it, which is remarkable. I really feel like I received an excellent treatment, and all doctors were caring and helpful. I cannot say to what extent my case is unique or not.

My mother does not fully share my opinion though, probably because she really had countless interactions with the NHS system which necessarily causes some frustration at some point. The worst part of the experience was probably visa related: when I was much younger there were issues with my expired visa, and at the time the need for intensive care is probably what allowed me to stay in the UK. But it eventually got sorted out.

Is there something you wish the NHS would have done differently/better?
No, not really. They did everything they could, and I am very grateful.

You study Physics in Uni. Any interest in genetics? do you follow the recent advances in the field?
I studied some biology. But I like the thinking process, not the extensive memorizing often associated with life sciences courses. I liked genetics though because it was less memorizing and more reasoning. But overall, mathematics and physics are more appealing to me right now.