Latest research led from Manchester could revolutionise the diagnosis of Perrault syndrome, a rare genetic condition that results in hearing loss. In women it also leads to early menopause or infertility. Perrault syndrome can be accompanied by learning difficulties, developmental delay and nerve damage.
Researchers at Manchester University NHS Foundation Trust (MFT) and The University of Manchester, with colleagues in Newcastle, Germany and the USA, collaborated with clinicians across the world to identify changes in two different genes, that both result in Perrault syndrome.
Funded by the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre (BRC), Action Medical Research, The Royal National Institute for Deaf people (RNID) and the Medical Research Council, the results from two separate studies, which identified changes to the DAP3 and MRPL49 genes, have been published in the American Journal of Human Genetics.
Professor Bill Newman, Consultant in Genomic Medicine at MFT, and Rare Conditions Co-Theme Lead at the NIHR Manchester BRC, who co-led the research, said: "Finding the causes of rare conditions like Perrault syndrome are the first steps in understanding why people are affected, providing clearer diagnosis, and developing novel treatments.
"Previously up to half of all people with Perrault syndrome could not have this diagnosis confirmed by a genetic test. These new discoveries through this research will provide an accurate diagnosis to more affected people."
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.
Sam's story
56-year-old Sam was diagnosed with Perrault syndrome when she was 28 years old, after being under the care of various hospitals to diagnose her rare genetic condition.
Sam is profoundly deaf and was fitted with hearing aids before the age of one, which is a common feature of the condition. Other symptoms that led to her diagnosis include short stature, very small ovaries and the absence of periods.
Sam was identified with a DAP3 genetic change through this research in August 2024.
DAP3 is found in every cell of the body and is important in a part of the cell called the mitochondria, often referred to as the powerhouses of the cell. Some tissues in the body are very susceptible to when the mitochondria do not work properly, and it is why researchers believe hearing and ovarian problems occur in Perrault syndrome.
Sam said: "When I was told I had DAP3 gene changes I was pleased as it helped me make sense of my symptoms and better understand Perrault syndrome.
"This research is incredible and will help others who are in a similar position to me. I struggled for years not knowing what was wrong with me so, I hope it will help others too - especially those who are younger so they can get an earlier diagnosis and access to the help they need.
"I would advise anybody who is concerned to get advice as soon as possible. Thanks to this research, family members will also be tested which will provide an early diagnosis for more people potentially affected by the condition."
This research will now be used globally to provide an accurate diagnosis for those at risk or undiagnosed with the condition.
Professor Ray O'Keefe, Professor of Molecular Genetics at The University of Manchester co-led the work. Professor O'Keefe said: "Genetic testing helps families to get diagnosed earlier and to access the right care and support sooner.
"When patients - particularly children, are presenting with hearing loss or changes on their brain scan, they can be genetically tested to see if their health problems are caused by changes in these genes.
"Genetic testing removes the need for unnecessary investigations, allows closer monitoring to spot problems earlier and enables accurate genetic counselling for other family members who may be at risk."
Dr Ralph Holme, Director of Research at RNID said: "We are delighted to have been able to support this important research.
"As ovarian problems are a key feature of the diagnosis, men are rarely diagnosed even though they have the same risk of being affected. Early, accurate diagnosis can result in improved hearing outcomes.
"Understanding rare types of hearing loss, such as Perrault Syndrome, also gives us important insights that may be relevant to more common forms of hearing loss."
Professor Newman, who is also Professor of Translational Genomic Medicine at The Manchester Centre for Genomic Medicine at The University of Manchester, added: "Although genetic research into Perrault syndrome is complex, this new information provides important pieces in the jigsaw. We are continuing to look at all the genes that cause Perrault syndrome as understanding how these genes are all linked together means that perhaps it would be possible to create a treatment that would work for all of them.
"We have also started to make hearing nerve cells from skin cells of individuals with Perrault syndrome. This is exciting as testing the cells that are actually affected by the condition will help us to develop treatments targeted to the correct cell type."
Both research papers are available to read in the American Journal of Human Genetics:
Bi-allelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered apoptosis and a Perrault-syndrome-spectrum phenotype (published 2 January 2025).
Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency (Published 4 March 2025).
