UK scientists have found that a 7,000-year-old genetic mutation is responsible for a rare form of hereditary motor neuropathy (HMN).
In a paper, published in the journal Brain, geneticists and clinicians from the University of Oxford and University College London who led the international study said they had found that the novel disease gene VWA1 was linked to the progressive condition HMN. The research was supported in part by the NIHR Oxford Biomedical Research Centre.
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.
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 United Kingdom. It is estimated that the genetic variants in VWA1 may be responsible for up to 1% of the unexplained HMN cases in Europeans.
One of the patients identified with the condition is seven-year-old Lucrezia, from Birmingham, who has been treated at Great Ormond Street Hospital 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. We had this terrible idea that she may end up in a wheelchair,” 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: “The project meant everything to our family. The mutation was so rare that we wouldn’t have been able to discover it without the research. So it meant giving us a shot of a diagnosis that otherwise we wouldn’t have known. We’re extremely grateful that we were considered as a family for this initiative. For us it’s extremely valuable.”
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.
Lead author on the paper, Dr Alistair Pagnamenta of the University of Oxford’s Wellcome Centre for Human Genetics (WCHG), said: “The causes of the most common single-gene disorders have already been found. The ones that are being discovered now are typically much rarer; it takes longer to find them and the variants often lie in difficult-to-sequence parts of the genome. So it was quite surprising here 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.”
Whole genome sequencing
So, why had this genetic mutation not been discovered sooner? “Most clinical DNA labs currently use exome sequencing which only targets the approximately 1% of the genome that actually codes for proteins and this method is less accurate at sequencing the regions peripheral to these coding regions where the primary VWA1 mutation lies,” said Professor Jenny Taylor of the WHG and the NIHR Oxford BRC’s Co-theme Lead for Genomic Medicine.
“In contrast, this variant is picked up a lot more efficiently by whole genome sequencing, which demonstrates the latter method’s value and the rationale behind the 100,000 Genomes Project,” she added.
Another reason why the variant was perhaps not picked up previously is that in the region this variant occurs, there is already a repeated sequence of 10 DNA letters; with this mutation, the researchers found a third copy of this GGCGCGGAGC motif.
By looking not just at the variant, but also at the DNA around the variant shared by the 10 families, the research team was able to estimate how old the mutation is and confirmed it to be what geneticists often refer to as a “founder mutation”.
Dr Pagnamenta explained: “By looking at how much DNA around the mutation is shared by these families we can estimate that it arose around 300 generations, or 7,000 years ago; the newer the mutation, the greater the amount of DNA around the mutation is shared. But like a pack of cards, the longer you shuffle them, the less chance that two adjacent cards will stay together.”
Where some genes are activated in different parts of the body; others are only ‘turned on’ in one specific kind of tissue. This particular gene is highly expressed in the tibial nerves which activate the muscles in the leg, so it made sense for VWA1 deficiency to cause a peripheral neuropathy.
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.”
Another patient found to have the condition is 71-year-old retired Royal Air Force worker Chris Parkhurst, from Aylesbury. He started noticing he had problems climbing stairs around 20 years ago. His mobility has deteriorated gradually since.
Chris says: “Everyone thought it was SMA (spinal muscular atrophy), but all the tests said it wasn’t. I’ve had MRI scans, diaphragm tests, breath tests and they’ve all proved to be normal. But my neurologist thought it was SMA, but in a different form.
“I got this invitation from Stoke Mandeville hospital to join the 100,000 Genomes Project. I took part because I wanted to know how someone who was pretty healthy and had not had any major issues could go this way. It was not in my retirement plans to be using a walking stick until I was well into my eighties. I knew there was something not right and no one could give me an answer. I really am pleased now that something has come of it. And I can see why you need to research these things.”
Dr Richard Scott, Clinical Director at Genomics England, said: “The fact that ten project participants were identified as having VWA1 gene mutations is yet another demonstration of the tangible benefits participating in the 100,000 Genomes Project can bring. Generating these rare disease insights through whole genome sequencing means that patients are more likely to receive diagnoses and effective, personalised treatments.
“The study estimates the VWA1 gene mutation to be responsible for up to 1% of the unexplained HMN cases in people of European origin, demonstrating how widespread its impacts could be. Think of the discovery as like a single key that could unlock hundreds of doors and provide answers for thousands of patients across the continent.”
A German group, led by scientists based in Tübingen, has made a similar discovery to the Oxford/UCL team, and their paper will be published in the same edition of Brain.