DECIPHER: Fuelling Rare Disease Research

More than 15 years ago, a hospital doctor realised that bringing people’s genetic data together could provide answers for families affected by rare diseases. With the help of the Sanger Institute, the DECIPHER project has been helping families ever since.

By Ali Cranage, Science Writer at the Wellcome Sanger Institute

When Eilidh was born, her condition wasn’t immediately apparent. She had a hole in her heart and a bacterial infection, but both of these are relatively common in newborns. Doctors ordered a chromosome test, which came back ‘all clear’, and so she was sent home. But, as she grew, she began to ‘collect’ other symptoms and miss her developmental milestones.

“We were first-time parents, so had nothing to compare our experience with, but gradually things didn’t feel as they should,” recalls her Mum, Valia. “She began missing the milestones in the little red book and falling behind her little baby peers. It was noted at her first couple of checks but we were told it was probably nothing, they all develop differently (true), she is just a little delayed and a little floppy (I guess….?), it could be her reflux (oh! that make sense), it could be the hole in her heart making her body work harder…”

But she fell further behind, and more tests were ordered. “We embarked on a very confusing journey of test after test, normal results, clear scans and more normal results. Being passed from one department to another, in and out of hospital clinics and community services.”

The investigations including scans, blood tests and genetic tests continued to draw blanks. Her story is a familiar one for many families affected by rare diseases.

“Living without a diagnosis can be very isolating, and especially as Eilidh was our first child, it was hard to tell if her symptoms, or more accurately things she wasn’t able to do, were anything to be concerned about. It wasn’t until we were entered on the DDD study (Deciphering Developmental Disorders) and found the SWAN UK community when she was around 18 months old that we really acknowledged we were not a typical family.”

Eilidh’s condition causes profound and multiple learning disabilities, issues with her heart and digestive system, and sensory processing difficulties. But the cause of her difficulties remained a mystery.

A diagnosis for a rare disease doesn’t always make a difference to the treatments offered, as in so many cases there aren’t specific treatments available, but for most families it still has a massive impact on their lives. It offers the chance to meet others with the same condition. It helps them get services and support – which are much harder to access when a child has an unnamed condition. A diagnosis opens the way to research studies and clinical trials that could, one day, offer new ways to treat and manage a condition.

Doctors suspected, as with most rare conditions, that Eilidh’s condition has a genetic cause. A single glitch in her DNA is responsible for her symptoms. Eilidh, like all of us, has 6 billion letters of DNA which make up her genetic code, or genome. Though over 99 per cent of the DNA in each of our genomes is the same as any other person’s, a tiny fraction is different, making us all unique. Less than 1 per cent may sound small, but it is millions of letters of the genetic code.

From millions, to one

Finding exactly which changes in DNA are the ones responsible for any particular symptom is no easy task – especially when the change is rare. Some conditions are so rare only a handful of people in the country, or even the world, are affected.

In part, finding a change responsible for a specific symptom is a process of elimination. If Eilidh has a particular genetic change also seen in hundreds of people, who don’t have any similar symptoms, then that change can usually be eliminated. Other changes might be in areas of the genome where the function is known, and not relevant to symptoms, so can also be discounted. But the data sifting processes can still leave a list with hundreds of potential DNA culprits.

The solution is to combine data from many individuals. If the same rare change in the genetic code is seen in three or four people, and they have the same combination of rare symptoms, then that change is the likely culprit; that particular genetic change is likely to be the cause of those symptoms.

But a doctor looking after rare disease patients in a hospital may come across some rare conditions only once in their lives.

To allow doctors and researchers to make these vital connections between patients with rare diseases, like Eilidh, Wellcome Sanger Institute scientists created DECIPHER.

The Human Genome Project

DECIPHER was created in 2004, shortly after the publication of the Human Genome Project – a momentous landmark in biology. Like most science, the Human Genome Project opened up more questions than it answered. For Helen Firth, consultant clinical geneticist at Addenbrooke’s Hospital in Cambridge, it opened up the possibility that the data could be used to help patients with rare diseases.

Helen met with Allan Bradley, the director of the Sanger Institute at the time, to discuss her ideas for DECIPHER. The Human Genome Project meant that for the first time it was possible to compare an individual’s genome sequence to the ‘reference’ human genome sequence, and map out every single difference.

Together with the Sanger Institute web team, Helen, Nigel Carter and Paul Bevan created DECIPHER to unite patients’ data from across the UK – both their symptoms and their genetic data mapped against the reference human genome. The aim was to understand the significance of genetic changes in health and disease.

It was one of the first times that data from the human genome project had been put to use in the clinic.

Coming in to focus

At that time, genomic array testing was just being introduced in NHS centres. An array detects if chunks of DNA are missing or duplicated, termed ‘microdeletions’ or ‘microduplications’. Resolution varied between different types, but DNA sections around 1,000,000 letters long could be detected. DECIPHER was a way for clinicians to view that data and begin to make sense of it. As genome sequencing became more common, moving from research laboratories into clinics, sequences came into sharper focus, with individual letters of DNA becoming visible.

Both the array data and genome sequence data results were unfamiliar to doctors. DECIPHER allowed them to connect with each other, to find others who may have seen the same thing and could help interpret the findings.

Open sharing

DECIPHER couldn’t exist without patients sharing their data. It’s what makes everything possible. Privacy is extremely important, and while information is shared, only the minimum amount of essential information is made available. No additional information about an individual is open to researchers, and all open data sharing is agreed by the patients who sign up.

“We are very grateful to the patients and families, clinicians, scientists, legal and ethical advisors who contribute to make DECIPHER such a powerful resource for diagnosis and discovery in rare disease. Sharing clinical features alongside key genomic changes is enabling us to discover which genetic changes are part of healthy variation and which cause disease.”

Dr Helen Firth, Consultant Clinical Geneticist, Addenbrooke’s Hospital & Clinical Lead for DECIPHER & DDD study

Each genetics centre maintains control of its own patient data or shares the data with trusted parties in a collaborative group, until patient consent is given to allow data (without identifying details) to become freely viewable within genome browsers.

Diagnosing Eilidh

Eilidh’s data was added to DECIPHER and four years after joining the Deciphering Developmental Disorders study, she got a diagnosis. The diagnosis came as a letter from her clinical geneticist, like any other appointment letter or test results.

“We hadn’t thought about it in a long time, we were getting on with our everyday lives,” recalls Vaila. “It was a bit of a surprise. Of course we immediately googled it. There was nothing we didn’t know already in terms of symptoms, but we did find a Facebook group in America. It’s allowed us to meet with other families affected by the same condition.”

Eilidh has KAT6A Syndrome, an extremely rare condition. There are a few hundred children world-wide who have a diagnosis, and probably 10 in the UK. Vaila, Eilidh and their family have met several of the families now.

KAT6A syndrome is caused by a change in the KAT6A gene. This gene has a role to play in controlling a whole range of other genes in the body, hence why the symptoms are so broad – though the full functions of the KAT6A gene are not known.

Dr Matthew Hurles, Scientific Lead for DECIPHER and the DDD study and Head of Human Genetics at the Wellcome Sanger Institute said:
“The first step in finding a cure is finding what the underlying cause of a disease is. Everything is critically dependant on that. From that point onward you can narrow in on the particular biology of the disease and what kind of drugs might be required in a particular cell type.”


DECIPHER has been up and running for 15 years. Every NHS genetics centre uses it, plus many clinics around the world.

“I now use it almost every day to interpret genomic changes that may be disease associated. We use it in the clinic for our multidisciplinary meetings and in research. I have used DECIPHER in many research papers. In my office DECIPHER is used as commonly as my coffee cup – that’s a lot!”

Professor David FitzPatrick, Consultant in Paediatric Genetics, University of Edinburgh

With more than 250 clinical centres inputting data, DECIPHER is the biggest database of its kind in the world, sharing genetic changes almost 30,000 patients. It links to other international databases too. Maintained and updated at the Sanger Institute, it’s free to use.

Over 2,000 scientific papers have been published based on DECIPHER data. Many researchers have used the data to discover new diseases.

“DECIPHER has been an enormous help for our work seeking genetic diagnoses for patients with rare disorders. It has provided a platform for the NHS labs to share genetic variant data as well as providing easy, highly effective visual access to data sets that are used for interpretation.”

Professor Sian Ellard, Scientific Director for the South West Genomic Laboratory Hub, Head of Exeter Genetics Laboratory and Professor of Genomic Medicine, University of Exeter

Eilidh’s diagnosis is still making a difference. New research on KAT6A was recently published in the USA, and her doctors here hope it will help with better ways manage her condition.

DECIPHER has facilitated diagnoses for thousands of families like Eilidh’s. As genome sequencing becomes routine in health services around the world for those affected by rare diseases, platforms such as DECIPHER that bring together the most up to date genomic and clinical information available will be vital.


Please note that recruitment for the DDD study is now closed. If you have queries and are already taking part in the DDD study, or other studies that use DECIPHER, please contact your genetics service. The Sanger Institute does not have access to individual patient details or results.