New tools for clinical genetics

Since the dawn of DNA sequencing technology, around 40 years ago, scientists have been figuring out how changes in DNA bring about changes in people. And as capacity has grown and costs have fallen, with the hundred dollar genome looming on the horizon, clinical geneticists are trying to use genomic data to diagnose patients with genetic diseases. To make this complex task simpler, Cambridge-based company Congenica has developed an online tool called Sapientia, which guides clinicians through the process of linking a genetic variation in a patient to the condition that’s affecting them. To find out what it can do for patients and their families, Kat Arney spoke to former geneticist and now chief operating officer at Congenica, Nick Lench.

Nick - So the problem that labs face now is that through the advent of whole exome sequencing, whole genome sequencing because of the massive amounts of data that are produced. It’s actually quite difficult to do that in a single laboratory. You want to be able to scale up the analysis and use sophisticated bioinformatics. So, we’ve developed a software to address that issue. It enabled the clinical scientists to make a rapid diagnosis on the patient.

Kat - So you're saying, “I've got this patient who’s come in to me. I've got their DNA sequence. What is it that’s wrong with them? What is it in their DNA that’s making them ill?”

Nick - That’s right. So you have to look at all the different DNA sequence variants that occur in the patient compared with the reference sequence, the reference genome, look at all those different variants. So for example if you compare two whole genomes, there might be as many as 4 million sequence variants between two individuals. How on Earth do you filter those 4 million down to a handful of potentially causative variants?

Kat - What sort of diseases and disorders are we talking about here?

Nick - So these are what we called rare inherited disorders. Most of these will manifest in children - up to about 80 per cent of all rare diseases will occur in children. For example, they may have features such as developmental delay when a child fails to meet their developmental milestones. Inherited cardiac disorders so maybe structural problems with the heart. There may be issues with inherited kidney disorders as well. So really, the whole spectrum, any organ system you can think of, there will be a genetic defect and a range of conditions that affect those organs caused by inherited disorders.

Kat - So with the software that you have, clinicians can go, “Okay, I think that this patient has this particular genetic change that is causing them this problem.” What do they then do with that information? Can it bring them a cure?

Nick - In most cases  the best outcome is a diagnosis. We are beginning to see more and more new therapies for patients with inherited rare diseases. The more information we accumulate about diagnosing these rare disease patients more we understand about the biology. And there's a lot of patient advocacy groups out there now who really want to look for new therapies. So for example, you might look at ways of repurposing existing drugs. There's quite a few nice examples. In the US, the Cystic Fibrosis Foundation has worked very closely with a pharmaceutical company to develop a novel therapy for CF. So that’s probably a really good success story of developing new therapies for a rare disease.

Kat - What about the cases where there is no treatments? What good does the diagnosis do for those families?

Nick - So I think it’s really important for all families to reach a diagnosis. If you talk to families that they want to understand why their child has a particular disorder. So if that’s due to an inherited condition, they can then use that information to help plan their lives for their children - so whether that would be receiving medical support, social support, educational support. And it also offers reproductive choices so again, if the mother wants to have a subsequent pregnancy then there are potentially options to ensure that that is a successfully pregnancy, an effective pregnancy.

Kat - So this kind of software where you can get the information, you can get a diagnosis, is that just useful for children, for adults? What sort of patient groups can this be used for?

Nick - It can be used for any patient group. What's really exciting is a new application in the field of neonatal intensive care. So this is where we see very, very poorly babies within a few hours of birth. If you're then able to do what we called a rapid whole genome sequence, you have the opportunity to make a diagnosis in a very short period of time, maybe within three to four days. And then in some cases, if you're able to have an early intervention that can absolutely have a fantastic effect on the outcomes for some of those babies. So it might be something as simple as a vitamin supplement and that can absolutely ensure that their brains develop in a normal way and they have all of their cognitive functions, whereas if you miss that and maybe 6 months, 9 months into life, it may be irreversible damage to the child. So it’s really, really important. Other applications might be where you can make a decision whether you have to give a child a heart transplant or a bone marrow transplant as well, so early diagnosis is critical. We’ll see more and more applications of whole genome sequencing and I think it will really benefit patients.

Kat - Say your programme finds a genetic change and says, “Okay, it’s this that’s causing the disease.” How do you know that for sure? What does a doctor do with that information? Do they just go, “Yep!” The computer says, “Ding! Off we go!”?

Nick - It’s really about building the body of evidence. So I think it’s a bit like innocent until proven guilty. So you take your DNA sequence variants and you build the case for, is it really that the causal variant that causes that particular phenotype in that patient. So most of the time, you're really looking to other reported examples. Has a patient like this been reported before? Have they got a mutation in the same gene? Have they got exactly the same mutation in the same gene? And so, you're sort of looking for other examples to back that up. Ultimately, what you want to be able to do is what we called functional validation so you can prove biologically that the alternation of that particular gene has a causal effect. But in reality, if within a diagnostic clinical setting, that’s not possible. It’s beyond the capability of the system and it’s expensive. So really, you're trying to build the evidence base and then you're effectively making a subjective decision and saying, “I think this particular DNA sequence variant causes the disorder in this patient.”

Kat - Nick Lench, chief operating officer at Congenica.