Ancient gene mutation found to cause rare hereditary condition

UK scientists have found that a 7,000-year-old genetic mutation is responsible for a rare form of hereditary motor neuropathy (HMN) – a progressive condition that affects the nerves leading from the spinal cord to the muscles in the limbs.

HMN 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.

In a paper published in the journal Brain, geneticists and clinicians from UCL and the University of Oxford said they had found that the novel disease gene VWA1 was linked to the condition.

Ten participants from the 100,000 Genomes Project, established to sequence the genome of patients affected by a rare disease or cancer, were identified as having VWA1 gene mutations – an unusually high number for a newly-described genetic condition.

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.”

Around one in a million people 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.

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”.

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.”

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.

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