Tilly and her family.
As a toddler, Tilly Douglas's blood sugar was so variable that she would sometimes have to be on a feeding tube while eating – and would still experience dangerously low blood sugar levels within an hour. She was a regular resident at Great Ormond Street Hospital.
Tilly lives with Congenital Hyperinsulinism – in which the pancreas releases too much insulin that lowers blood sugar. If the condition is not treated appropriately, the brain can be starved of vital fuels, which can cause learning difficulties or even death.
When the limited treatment options failed, Tilly had to endure having 85 per cent of her pancreas removed, in a major operation, particularly for a two-year-old.
Tilly's mother, Georgina Douglas, recalled: "In the early days, I was mostly in shock. Tilly's blood sugar was very low indeed – she was always on cannulas, but still having dangerous 'hypo' attacks brought on by low blood sugar. She was in Great Ormond Street a lot, and at one point she had to be transferred to Berlin, which was the closest place that could do a PET scan at the time. It was all pretty terrifying."
Georgina, who lives near Sittingbourne in Kent with husband Aaron, Tilly and her sister Martha, 7, said: "One of the really difficult things was not knowing. We had to take a best guess that the pancreas operation was the right thing to do. It was a big operation for a toddler. It did improve things for Tilly, but it wasn't a cure."
Now 15, Tilly lives in a typical teenage world of music, Netflix and GCSE revision - but she still endures a plethora of health problems, including gastric issues. However, she hopes future children may benefit from a major genetic breakthrough at the University of Exeter, which she helped to bring about.
Tilly had her genome sequenced by a world-leading research team at the University of Exeter, in a bid to try and find the cause of her congenital hyperinsulinism. A condition which scientists have been unable to find the route cause in up to half of cases.
Her family also allowed a proportion of her removed pancreas to be analysed, to allow the team deeper insight into what happens in the body in Congenital Hyperinsulinism.
The cooperation of families like the Douglases has helped the Exeter team discover a cause for Congenital Hyperinsulinism that could one day lead to new treatments – and could also unlock the cause of a number of other rare genetic diseases.
Lead researcher Dr Sarah Flanagan, at the University of Exeter Medical School, explained: "We've really struggled to work out what's going on in the 50 per cent of babies with no known genetic cause of Congenital Hyperinsulinism. We've been looking at the DNA from these patients for years, but the cause of disease remained frustratingly elusive."
Thanks to Tilly and others who took part in the research, the team made a revelation that is rewriting science.
Until now, most genetic breakthroughs have centred around the exome - the region of the genome that generates proteins such as insulin. Typically, scientists will sequence the genome of individuals with a rare disease and will look for variants in the DNA that affect a protein known to have an important role in the organ that is relevant to the disease
However, in Tilly and 16 other children, the genetic analysis revealed a variant outside of the exome – the first time this type of variation has been discovered to cause disease. The impact of the genetic variants was that a gene called HK1 was behaving differently in patients with Congenital Hyperinsulinism. The gene, which leads to insulin being produced even when blood sugar levels are low, is usually silenced in the pancreas. But the team found it was active – meaning it was working to lower blood sugar to dangerous levels. Studying Tilly's pancreatic tissue confirmed this hypothesis.
"It's incredibly important to be able to provide answers to parents who have been desperate to know the cause of their child's condition," said Dr Flanagan. "These findings also pave the way for improved treatment of this condition with the development of drugs that inhibit HK1, and consequently insulin production, being a real possibility."
"Even more exciting is the potential for this approach to unlock causes of other genetic conditions. We now know that we need to look across the whole genome for genetic changes to find the answers we need, and specifically turn our attention to the proteins that are silenced in the disease-relevant organ tissue. That approach could rapidly advance genetics and provide answers, and better treatments."
Georgina Douglas said: "We're really pleased to have contributed to this breakthrough. It would have been so valuable to know the cause of Tilly's condition, and it could have helped guide our decisions. Hopefully, over time, we'll see more findings emerge, and maybe even a treatment."
Tilly added: "I'm delighted to help other people through this research. I've learned to live with Congenital Hyperinsulinism, and sometimes it's hard, but I don't know anything else. I hope it can contribute to making things easier for other families."
The paper is entitled 'Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism', published in Nature Genetics.
