Thanks to a team at the University of Leicester, families living with nystagmus were included in the 100,000 genome project. In an article by our Head of Research, read how this has supported new discoveries and brought us closer to gene therapy for nystagmus.
Launched over a decade ago, the 100,000 Genomes Project (100KGP) was a landmark undertaking for the NHS. The project sought to map the DNA of 100,000 patients with rare diseases and their families as well as patients with common cancers. By combining this with clinical information about the patients’ conditions, researchers hoped to bring new insights into causes, potential new ways of diagnosing them, the development of new drugs and new uses for existing drugs and, ultimately, a way of predicting and preventing illness. It would also pave the way for personalised ‘genomic’ medicine.
A group from the University of Leicester, including Professor Irene Gottlob and Dr Mervyn Thomas, successfully petitioned for infantile nystagmus to be included, giving patients access to whole genome sequencing (WGS) for the very first time[1].
As part of the East of England NHS Genomics Medicine Centre, the team went on to lead the 100KGP strand on infantile nystagmus, which began in 2015. At the Nystagmus Network, we are aware of many families who took part in the 100KGP. If you would like to share your story with us, please get in touch.
How many genes?
When doctors diagnose nystagmus using genetic testing, they don’t usually look at the whole DNA but only a fairly narrow range of genes known to cause the condition. This is a quicker process, but still leaves a high proportion of cases without a known cause. But what if nystagmus is actually far more complex, genetically, than we thought? Here was the opportunity to look again at diagnosing the genetic cause of nystagmus.
Building on the 100KGP, Dr Mervyn Thomas and Dr Mahmoud Fassad from Leicester undertook the largest infantile nystagmus genetics study worldwide to date, with 473 patients from 388 families. They compared their gene panel tests with their 100KGP results and thereby widened the number of genes examined.
Using WGS, the research team uncovered several groundbreaking insights:
More cases successfully diagnosed
46% of people who took part in the study (218 people) received a confirmed diagnosis. For many families, this ended years of not knowing what had caused the nystagmus.
“These results show that using full genome testing can save patients months and even years of misery when it comes to diagnosing complex eye conditions,” said Dr Mahmoud Fassad.
Previously undetected mutations found
45 families had mutations in 36 genes which were not included in the gene panels. Without WGS these cases would not have been discovered.
Dr Mervyn Thomas said: “This study showed that the genetic architecture of infantile nystagmus and albinism is far more complex than previously appreciated and therefore standard gene panels are simply not enough.”
Identifying the most common cause
The study highlighted a specific pattern in the TYR gene which is usually overlooked. The project revealed it to be the single most common genetic cause of nystagmus in the study group.
Related health conditions
The data proved that finding the exact gene variant can alert doctors to potentially broader, interconnected health issues early on. For example, there was evidence of significant links with:
- Foveal hypoplasia (underdevelopment of the central retina)
- Severe refractive errors (astigmatism and extreme short or long sightedness)
- Strabismus (squint)
- Neurodevelopmental features and hearing loss
“The breadth of diagnoses found, including rare syndromes and dual diagnoses, makes a compelling case for whole-genome sequencing as the first-line diagnostic tool,” said Dr Thomas.
Finding specific hotspots
The FRMD7 gene is known as a major cause of X-linked nystagmus. What studies have shown since 100KGP is that there are two distinct hotspots for mutations.
The findings have already made a difference to families and patients.
What this means for families
Cases of nystagmus and associated eye or wider health conditions may be diagnosed much earlier. More cases have a known genetic cause rather than being listed as ‘idiopathic’ (with no known cause), as more genes are now recognised as potential triggers for nystagmus.
According to Dr Thomas the study should lead to improved clinical care, provide families with clearer information about inheritance patterns and future pregnancies and help patients access emerging gene-targeted therapies and clinical research opportunities.
Dr Thomas wishes to acknowledge that the early small grant provided by the Nystagmus Network and Fight for Sight funded the creation of the very first nystagmus gene panel [2]. “That was my very first grant,” he said “and the learning we gained from that work has been instrumental in reaching this point. Thank you, as always, for your support and for providing those vital seed funds.”
The Nystagmus Network’s response
“Following decades of steady improvements in the way nystagmus is diagnosed in children, the 100KGP and this new study by the Leicester team have transported us into a new era. No longer do families have to accept a ‘don’t know’ answer. Instead, we have a strong argument for full genome testing, bringing hope of genetic therapies that bit closer.”
Sue Ricketts, Head of Information, Networks and Research
References
1 https://iovs.arvojournals.org/article.aspx?articleid=2767495
Further reading
100,000 Genomes Project https://www.england.nhs.uk/genomics/genomic-research/100000-genomes-project/
100,000 Genomes Project – Paving the way to Personalised Medicine https://webarchive.nationalarchives.gov.uk/ukgwa/20171102123005/https://www.england.nhs.uk/publication/100000-genomes-project-paving-the-way-to-personalised-medicine/
Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing https://www.nature.com/articles/ejhg201744
Genome-wide testing brings faster diagnosis https://www.opticianonline.net/content/news/genome-wide-testing-brings-faster-diagnosis
Genome-wide testing improves diagnosis of inherited eye conditions, study finds https://www.insightnews.com.au/genome-wide-testing-improves-diagnosis-of-inherited-eye-conditions-study-finds/
New study shows that broader DNA testing is needed to diagnose complex eye conditions https://le.ac.uk/news/2026/june/eye-condition-genome-testing-leicester
Whole-genome sequencing uncovers diverse genetic causes and phenotypic signatures in infantile nystagmus and albinism https://www.nature.com/articles/s41525-026-00580-1
