Manchester-led research finds surprising cause of rare inherited condition linked to hearing loss and infertility

Researchers at Manchester University NHS Foundation Trust (MFT) and The University of Manchester (UoM) continue to revolutionise the diagnosis of Perrault syndrome, with the latest discovery of a new genetic cause for the rare condition linked to hearing loss and infertility.  

While previous groundbreaking research had linked the condition to changes in some genes, several patients had still been unable to get a confirmed genetic diagnosis – until now.  

In new research co-funded by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre (BRC): Manchester, RNID with support from The Freemasons’ Charity and Medical Research Council, the results published in the American Journal of Human Genetics, identified another gene causing the same condition but through a completely different biological pathway. 

Bill Newman, Consultant in Genomic Medicine at MFT and Professor at UoM, who led the research, said: 

This research gives long-awaited answers to families who previously had no explanation for their condition and could prevent unnecessary investigations for individuals.  

“Knowing the exact genetic cause of the condition can help clinicians monitor hearing, development, and hormone health more closely; and provide earlier and more tailored support. It also enables accurate genetic counselling for other family members who may be at risk.”  

The study 

Researchers at MFT and UoM, collaborated with colleagues in Newcastle, Dublin, Pakistan, Australia and the United States of America (USA). 

They studied three different families in Pakistan, Ireland and Australia, with Perrault syndrome, who did not have changes in the known genes.  

All affected individuals had severe hearing loss and ovarian problems (in women). Some also had neurological symptoms such as balance difficulties (ataxia) or mild intellectual disability.  

Using genetic testing they discovered that all 13 affected individuals had changes (variants) in a gene called GPN2 and that the condition is inherited when both parents carry the gene change. 

Professor Newman, who is also the Rare Conditions Co-Theme Lead at the NIHR BRC: Manchester, continued: “The changes in GPN2 affect a completely different biological process than the genes that have previously been linked to Perrault syndrome. This suggests that disrupting different pathways can lead to the same health problems but may require different approaches to treat them.” 

The next steps for the researchers are to identify more patients and families with Perrault syndrome due to changes in the GPN2 gene. The researchers believe the further understanding of the condition and its causes will lead to the development of better, targeted treatments.  

Ralph Holme, Director of Research at RNID, said: “This research is an incredibly exciting breakthrough, and represents a major step forward in our understanding of Perrault syndrome. The identification of a new gene associated with hearing loss not only means more people can now get an accurate diagnosis of the cause of their hearing loss, but it also provides vital insights that could pave the way for treatments for Perrault syndrome and other more common forms of hearing loss in the future. We are delighted to co-fund vital research like this to help to improve understanding of hearing loss and bring us closer to more effective treatments.”  

The results from the study “Biallelic missense variants in human GPN2 result in Perrault syndrome” have been published in the American Journal of Human Genetics: https://www.sciencedirect.com/science/article/pii/S0002929726002260.  

Initial research into the condition began in 2011 at The Manchester Centre for Genomic Medicine, Saint Mary’s Hospital, part of MFT, when researchers led by Professor Newman undertook genetic studies on a local family with Perrault syndrome.  

Their research identified a novel gene and changes within the gene which led to the diagnosis of the syndrome. Further studies by the Manchester group and other researchers around the world have found eight different genes that cause Perrault syndrome.   

Read more on the previous Perrault syndrome gene discovery.