Helen Firth, a clinical geneticist at Cambridge University Hospitals, has spent her career trying to help those affected by rare diseases.

“Once you’ve got a diagnosis, you can try and learn from other patients with that condition about what the future might hold,” she says. This is so you can try and tailor future medical surveillance and management of the disease, she adds, as well as “provide accurate advice to other family members about the chances of another child or family member being affected by the condition”.

Yet, despite her best efforts, for many years Firth could only diagnose about a quarter to a third of the patients coming through her doors. Traditionally, geneticists like Firth used a process called karyotyping, which involves pairing up and ordering all the chromosomes to see if any are missing, duplicated or contain subtler structural changes.

Karyotyping remains a useful technique for pinpointing large abnormalities, but the level of resolution is limited to around 5 million base pairs. Geneticists’ work became easier with the development of array technology, which enabled smaller abnormalities to be detected, with a resolution of 50,000–100,000 base pairs.

However, neither of these techniques could spot tiny (but often very significant) changes, such as a single chemical letter being substituted for a different one. For this, you need DNA sequencing, a technique first developed during the 1970s. The initial sequencing of the human genome took around 13 years and cost more than £2 billion. The process has become progressively faster and cheaper ever since.

Even so, until very recently it was only practical for clinical geneticists to sequence one gene at a time — limiting what could be achieved in an individual patient.

However, by 2010 array technology had improved and the cost of genome sequencing fallen to the point where Firth, together with Matt Hurles — who is now Head of Human Genetics at the Wellcome Sanger Institute — believed they might be able to diagnose many more patients if these technologies were systematically applied.

So, in partnership with NHS Genetics Services and several other research groups, they recruited more than 12,000 British children and adults with undiagnosed developmental disorders into the Deciphering Developmental Disorders (DDD) study and sequenced all the gene-coding regions of their DNA. They also sequenced their parents’ DNA, enabling them to identify mutations that had occurred ‘de novo’ — either during egg or sperm production or when the affected person was still an early embryo.

“The question with these families has always been why so many of them have one very sick child and everyone else is healthy,” says Hurles, who leads the DDD study. “What we’ve found is that when we can make a diagnosis in these children, it’s often because of one of these new mutations.”

One of those recruited was Evie Walker. She and her parents each gave a saliva sample, and the genetic sequence of each of their 20,000 genes was compared to a database of 1,450 known developmental disorder genes. Although doing this has enabled many DDD participants to receive a diagnosis, it didn’t work for Evie. Instead, for Evie and those like her with no diagnosis in the DDD study, the researchers turned to her other genes — those with no known link to disease — looking for ones containing a significant excess of de novo mutations.

This led them to the PURA gene, which encodes a protein that helps regulate the expression of numerous other genes. Evie and two other girls were found to have small deletions or spelling mistakes in different areas of the PURA gene, which the researchers believed accounted for their illness.

Although the girls had similar symptoms, they weren’t identical: “We’re often finding that these disorders are quite variable from one patient to the next, and this might be one reason why they haven’t been recognised before now — because a clinician couldn’t have said: these are all one thing,” says Hurles.

To date, rare variants in nearly 1,500 genes have been shown to cause developmental disorders. So far, the DDD study has identified 30 new genes associated with developmental disorders and has led to the recognition of 14 entirely new disorders — although the data is still being analysed and more are likely to emerge.

“It has been wonderful to have families who I struggled for years to get a diagnosis for recruited to the DDD study, and then to have been able to sit in clinic with and actually explain the molecular diagnosis to them,” says Firth.

As for Alison Walker, though she wanted a diagnosis for Evie, she underestimated the impact it would have on their lives: “We thought it would just be a name for what we were already living with. We didn’t expect it to be life-changing, but then when it came it really was.”