First children receive a genetic diagnosis at GOSH as part of the 100,000 Genomes Project

The first children to receive a genetic diagnosis through the 100,000 Genomes Project have been given their results at Great Ormond Street Hospital (GOSH), part of the North Thames Genomic Medical Centre (NTGMC.)

The results, which pinpoint changes in different single genes as the cause of two previously undiagnosed conditions, come from the first wave of families recruited as part of the pilot phase of the project. These patients came from across the UK, some travelling long distances in order to take part in the rare genetic disease aspect of the pilot, which was led by GOSH.

As well as removing a large amount of uncertainty for the families, the results stand to have a major impact on many areas of their lives including future treatment options, social support and family planning. They also have the potential to help many more children with undiagnosed conditions who may be tested for these genetic mutations early on and be offered a diagnosis to help manage their condition most effectively.

The main 100,000 Genomes Project, launched in December 2014, set out to sequence 100,000 whole human genomes to help researchers and clinicians better understand, and ultimately treat, rare and inherited diseases and common cancers. The programme is now well established across the country with the NTGMC recruiting more than 100 families a month.

The North Thames Genomic Medicine Centre is co-ordinated by GOSH in collaboration with partners University College London Hospital NHS Foundation Trust (UCLH), the Royal Free London NHS Foundation Trust, Barts Health NHS Trust, Moorfields Eye Hospital NHS Foundation Trust and London North West Healthcare.

Professor Lyn Chitty, a clinician at GOSH and clinical lead for the NTGMC, says: “It’s really exciting to see the results coming through and the difference this can make for families. It increases confidence in the project and shows that the application of genomics can live up to the promise of changing the way we diagnose and treat patients in the future.”

Researchers also hope that the positive results will help to encourage more clinicians to refer patients to the project so that a greater number of families can be tested and helped.

GOSH Consultant in Clinical Genetics, Professor Maria Bitner-Glindzicz says: “With undiagnosed genetic conditions it really is a case of the more families we test, the more we can diagnose. In order to confidently say that a particular gene is likely to be the cause of a condition and not just natural variation that we see in everyone’s genes, we have to match up gene mutations and symptoms across several children to find common features. The more children we therefore have to cross check against, the more likely it is that we can find these common features and give a diagnosis.”

Secretary of State for Health, Jeremy Hunt said: “Ground-breaking outcomes like this one for Georgia and her family are incredibly promising, and are the reason that this Government has invested over £200 million in bringing such revolutionary science to the NHS.

“By sequencing DNA on an unprecedented scale, we are also cementing the UK’s position as a world-leader in 21st century medicine”.

Professor Mark Caulfield, Chief Scientist at Genomics England, adds: “It is our aim to bring new diagnoses and, if possible, identify potential therapies for participants in the 100,000 Genomes Project. This is a pioneering project that will transform the application of genomics in our healthcare system.”

NHS Chief Scientific Officer Professor Sue Hill, OBE, responsible for the NHS Genomics Programme, said: “This is an excellent example of how whole genome sequencing can finally provide the answers that families have been seeking out for years. These new insights set them free to make decisions about the treatment options for their child and how they move forward with future plans for their family.

“The 100,000 Genomes Project has put the NHS at the forefront of science, expanding on medical diagnosis and providing a personalised medical treatment plan based on the information that comes from their genome.

“The more people who come forward to participate in the Project, the greater the body of knowledge there will be to inform diagnoses and patient care in the future.”

Georgia's story

"When Georgia was born by c-section in June 2011 we had 20 blissful, worry-free minutes enjoying our first born child and then our world was shattered," says Georgia's mum, Amanda. "The curtains were drawn round my bed and we were told that there may be a problem. A number of tests were carried out but all came back clear so we were discharged feeling apprehensive.

"As a first-time mum, I didn’t know what was normal but at around three months old I remember picking up another child the same age as Georgia and I just knew straight away from holding the baby that there was a difference between them and Georgia. The other child had started to gain strength and tone in their body while Georgia was very floppy.
After that we quickly noticed that Georgia wasn’t meeting any of her milestones and by six months, she wasn’t flourishing and was very poorly with lots colds and sickness. At this stage our paediatrician suggested that her problems were likely to be in her genes. Basic genetic testing brought up nothing and so doctors explained that she was now in the realms of an undiagnosed genetic condition. I had no idea that it was possible to have an undiagnosed condition. I thought you get told you might have a genetic condition, you have the genetic test, and then you get the answer.

"Being told that Georgia had an undiagnosed condition was one of the hardest points of our lives as we felt like we were alone. We looked for support from various groups but without knowing Georgia’s condition there wasn’t anywhere we fitted in. We then found out about SWAN UK (Syndromes Without A Name) and discovered that around 7,000 children a year in the UK are born with a genetic condition that can’t be diagnosed.

"Finding them was a real breakthrough moment and immediately it made life easier. Finding that other people are going through the same thing makes you feel that ‘if they can do this, we can too.’

"Between ages of one and two, we discovered all the problems Georgia had one by one. As well as both physical and mental developmental delay, we found that she has a rare eye condition that affects her sight; her kidneys don’t function properly and she has verbal dyspraxia, meaning we don’t know if she will ever talk.

"It’s very hard living with an undiagnosed child. It’s a constant rollercoaster of being tested for large numbers of horrific conditions before being given the all clear. It’s difficult to get support in the form of community nursing and schooling when you don’t fully know what’s wrong and you don’t know if your child is receiving the treatment they really need. Without a diagnosis, you also don’t have a prognosis so you don’t know what the future will hold for your child. Basic hopes for health, growth and development are all uncertain and we don’t even know if she will have a normal life expectancy.

"When Georgia was two we enrolled on a study, which looked at part of her DNA called the exome. It was thought that the exome carried all the most important information within it. But after two years after waiting, nothing significant had been found within Georgia that could explain her condition.
We then heard about 100,000 genomes project, which set out to have the most advanced and in-depth look at a person’s DNA by analysing the whole genome. As soon as I heard about the project, I wanted to get on it. I thought ‘if anything is going to get us an answer then we’ll try it'.

We came to GOSH and met with Maria Bitner-Glindzicz who talked us through the project. We were really keen and wanted to get signed up and on the pilot study straight away so we gave samples of all our blood on the same day.

"As soon as we were on the project I felt a huge sense of relief. I felt that they now had all the information needed to look at the full picture and it just required someone to decipher and understand it. There’s nothing else we could do or give and there would be no other secrets to unlock with Georgia. They had her genome and so the answers had to be there somewhere.

"I felt confident that they would find something one day but we didn’t know whether it would be in six months or 10 years. As we were one of the first families on the project, there were just no guarantees.

"It was almost exactly a year until we received a phone call from Maria. When she said that they’d found something it was one of the biggest days of my life. She explained that they had found a mutation in one half of a single gene in Georgia, which was likely to be the cause of her problems.

"Despite finding the mutation Maria explained that we all have genes that have been copied incorrectly and have mutations, but a lot of them are insignificant and don’t matter. They therefore had to cross check with other children with the same mutation to see if that particular gene change is likely to be causing problems. After finding two or so other children who had the same gene change and a similar neurological condition, doctors felt relatively confident that this gene was key to Georgia’s condition.

"They will probably find many more children with the same condition now as when they see a child with a neurological condition, they can check for this gene to start with.

"The diagnosis is going to change quite a few things for us. We always thought we’d have another child but because it was unknown if this was an inherited condition we were told that the chances of reoccurrence could be as high as 1 in 4. We held off expanding our family because of this but have now been told that we only have a 1 per cent chance of this happening again. The risk is still slightly higher than average so we have been offered a test bespoke to me that will check for that gene fault early on in pregnancy.

"As for Georgia, we are hoping that over time we will find out more about her condition and her prognosis. We also hope to connect with the other families that have children with the same gene change. It’s going to take time to find out more about this gene and what it controls and affects but I’m sure they’ll find more out. Medicine is not yet at the stage to offer genetic therapy but we have come so far in Georgia’s lifetime already that who knows what the future holds."

Jessica's story

"I had an uncomplicated pregnancy and was well throughout," says mum, Kate. "I even enjoyed it! When Jessica was born, everything seemed fine but by the time she was a year old we could tell that she wasn’t moving around as much as other children. At around 10 months she was just starting to sit up when some of her contemporaries were already starting to walk.

"We could see she was behind on all her milestones and at 13 months old she had her first seizure. We were told that they may be febrile convulsions, something that can be quite normal in small children, but when the seizures became more and more frequent we could tell something wasn’t right.

"Doctors couldn’t tell us what was wrong but said that a diagnosis didn’t really matter as they could just treat Jessica’s individual symptoms. But you can only go so far treating symptoms and we felt that it really mattered having a diagnosis.

"It’s the not knowing that I found really difficult. Most children with an undiagnosed condition have developmental delay, epilepsy and a squint – all of the things that Jessica has – so if you Google that you get umpteen possibilities. We spent hundreds of hours researching online and wondering ‘is it this terrible syndrome; is it that terrible syndrome?’

"After lots of invasive tests, we were told that Jessica had an undiagnosed condition. As soon as we knew this we became a part of SWAN UK who support families who have undiagnosed conditions.

"At a SWAN organised information day for families, a representative from the 100,000 Genome Project spoke about what the project was and how it might help families. We were really keen to join the project as by that point we’d already got to the end of medical testing and we didn’t have any answers. We had had so many tests and we felt like this was our last hope to find out what was wrong with her.

"The project involved coming to GOSH on a Saturday and donating blood samples from Jessica and both of us parents so that they could test what was different in her genes compared to ours.

"It was really easy taking part. We came to GOSH to have our blood taken and that was it. We didn’t need to come up to the hospital again until we got a result. We would recommend it to anyone.

"After a two year wait, we got a call to say that they had found a genetic error in Jessica that isn’t shared by either me or her dad. The gene error and associated condition, called GLUT1 Deficiency Syndrome, means that her brain doesn’t have enough energy to function properly.  We had always been worried that something preventable happened during the pregnancy or at the birth to cause Jessica's problems and it was such a relief to know there's nothing we could have done differently.

"Now that we have this diagnosis there are things that we can do differently almost straight away. Her condition is one that has a high chance of improvement on a special diet, which means that her medication dose is likely to decrease and her epilepsy may be more easily controlled. Hopefully she might have better balance so she can be more stable and walk more. She’s now four years old and still looks like a wobbly toddler trying to move around!

"A diagnosis also means that we can link up with other families who are in the same boat and can offer support. The condition is still quite rare but there are definitely other children out there who have it. I’m really looking forward to saying ‘we are one of you; we have this problem too!’

"The results are also going to be very useful for family planning. If we had had another child before, we didn’t know if they would certainly be affected by the same condition or if there was only a small chance. I think we can now say that there is only a tiny chance.

"More than anything the outcome of the project has taken the uncertainty out for us and the worry of not knowing what was wrong. It has allowed us to feel like we can take control of things and make positive changes for Jessica.

"It may also open doors to other research projects that we can to go on. These could be more specific to her condition and we are hopeful that they could one day find a cure."