Ancient gene mutation found as the cause of rare hereditary condition for GOSH patient

HMN affects the nerves leading from the spinal cord to the muscles in the limbs, and causes muscle weakness and affects movement in the feet and legs. Onset of HMN often occurs in teenagers, although it can happen later in life.

Ten participants from the 100,000 Genomes Project were identified as having VWA1 gene mutations – an unusually high number for a newly-described genetic condition. The 100,000 Genomes Project, was established to sequence 100,000 genomes from NHS patients affected by a rare disease or cancer, and has now paved the way for the UK’s new Genomic Medicine Service. Great Ormond Street Hospital (GOSH) was named as a key centre co-ordinating the recruitment of patients to the project in 2014. This means that many of our patients took part in the project and had their whole DNA analysed or ‘sequenced’.

One of the patients identified with the condition is seven-year-old Lucrezia, from Birmingham, who has been treated at GOSH since 2018. She finds it hard to climb stairs and to run. Because doctors were unable to diagnose her condition, they recommended she join the 100,000 Genomes Project. Lucrezia’s family were delighted to finally get answers when the mutation was found in March 2020.

“In the past nobody could tell us if she was going to progress. We wondered what we would say to her when she grows up and asks about her disease," her mother, Francesca, said. “You see how much she likes going around on the scooter and coming for walks with us, and you wonder whether she would be able to do this in the future.

“For us, when we saw the results of the genetics, it gave us a very positive message. Very few of these other cases progressed toward significant disability. I want her to maintain capabilities as much as possible. We’re definitely thinking in a more positive manner.”

Francesca says the research has had an important and immediate impact on their quality of life:

As for the future, knowing that Lucrezia’s condition is caused by a recessive mutation inherited from them, her parents would now like to know about the risk of Lucrezia passing the mutation on to her own children.

It is believed that one in 500 people of European origin carry the primary gene mutation, and around one in a million are affected by the condition, which translates to more than 60 people in the UK. It is estimated that the genetic variants in VWA1 may be responsible for up to 1% of the unexplained HMN cases in Europeans.

Lead author on the paper, Dr Alistair Pagnamenta of the University of Oxford’s Wellcome Centre for Human Genetics (WCHG), said: “It was quite surprising that in the 100,000 Genomes Project database, we found ten different families all with this new genetic disease. For a rare disease, this means it is actually relatively common.”

Prof Henry Houlden, Professor of Neurology at UCL, said: “The VWA1 gene is important in many ways that range from understanding the pathophysiology of hereditary motor neuropathy, to accurately diagnosing patients, many of whom may have had to wait many years to know the exact cause of their condition.

“This is a team effort, where the real players are our analysts and research fellows, and an excellent example of collaboration between Oxford, the 100,000 Genomes Project and UCL.”

The research was supported in part by the NIHR Oxford Biomedical Research Centre.