Impact case study database

Impact of genetics on diagnosis

Prior to the discovery of the FRMD7 gene as a major cause of infantile nystagmus, a range of lengthy testing procedures were required to diagnose DRDs, which could be particularly challenging in young children and distressing for parents. Genetic testing provides a more sensitive, cost-effective alternative for diagnosis that is less time-consuming and onerous for the patient and their families [E2]. Since uncovering the FRMD7 gene as a major cause of infantile nystagmus [R1], the UEU have built a strong portfolio of translational research by implementing clinical testing through single gene-based approaches and multigene panels using next generation sequencing.

The UEU developed the world’s first “nystagmus gene panel” [R3, G5], which simultaneously tests multiple genes (including the FRMD7 gene) associated with nystagmus using next generation sequencing. This method of testing now forms the basis of nystagmus genetic testing in the NHS and around the world. Within the UK, this is implemented locally or accessed via genomic laboratory hubs. Data capture from individual clinical genetic labs in the UK and France have shown that testing has been performed in over 1,400 patients with nystagmus. Worldwide testing is performed in multiple centres in over 14 countries [E1].

At a national level, the UEU have been pivotal, not only in disease nomination, but in also devising a virtual gene panel for infantile nystagmus as part of the 100,000 genomes project. The virtual gene panel forms the basis of clinical genetic testing and includes the FRMD7 gene and crucial genes highlighted in our nystagmus gene panel. This can also be accessed via PanelApp, which is an online open access tool permitting gene panels, such as the nystagmus gene panel, to be shared, downloaded and viewed by the scientific community; >3,000,000 requests have been made by over 17,000 unique visitors [E1b, G5, R3]. The use of genetic testing has been captured through questionnaires distributed to international centres for patients with nystagmus and DRDs [E2]. These indicate that not only does it result in earlier diagnosis but that in 15-25% of cases, the initial clinical diagnosis was revised because of genetic testing [E1b, R3]. The work, led by the University of Leicester, on development and clinical validation of the nystagmus gene panel has formed the basis of guidelines for nystagmus clinical genetic testing in countries such as the USA, Netherlands and South Korea [E2].

Accurate diagnosis of DRDs is challenging with misdiagnosis being a common problem. Other causes of nystagmus such as neurological disorders and syndromes are important to exclude. As outlined in clinical guidelines published by the American Academy of Ophthalmology in February 2020: “Genetic testing plays an important role in establishing the final diagnosis of infantile nystagmus … FRMD7 infantile nystagmus (FIN) must be confirmed with genetic testing for FRMD7 *mutations” [E3]**. One paediatric ophthalmologist from the National Eye Institute, USA has stated: “We use genetic testing as one tool to help differentiate retinal dystrophies from other forms of nystagmus, the genetic testing has been critical” [E2]. Guidance published by the American Academy of Ophthalmology in February 2020 stated: “Genetic testing plays an important role in establishing the final diagnosis of infantile nystagmus … FRMD7 infantile nystagmus (FIN) must be confirmed with genetic testing for FRMD7 mutations” [E3].

Impact of High-resolution imaging studies on diagnosis and patient outcomes

The Leicester Grading System (LGS) was devised to quantify the severity of delay in foveal development based on a series of ground-breaking studies that characterised foveal abnormalities in DRDs for the first-time using OCT [G1-G4]. These studies included disorders such as FRMD7- [R3] and PAX6- associated nystagmus, albinism and achromatopsia. The simple-to-use system allows the fovea to be assessed in minutes and is now used widely by ophthalmologists around the world as an extension of their clinical exam [E2]. A paediatric ophthalmologist from University of Ulsan College of Medicine, South Korea has stated: “The LGS has enormously helped us classify the severity of foveal hypoplasia and predict the later visual acuity, especially in patients with aniridia, infantile nystagmus, albinism, and prematurity. I am a huge proponent of the grading system”. A paediatric ophthalmologist at the Bartiméus Diagnostic Centre for Complex Visual Disorders, Zeist, Netherlands said: “ Since the publication of the 2011 paper on grading of foveal hypoplasia, we use the grading system routinely in our clinical practice” [E2].

The LGS is a key element of new clinical schemes for the diagnosis of DRDs [E4] including albinism as indicated in the Filière Santé Maladies Rares Dermatologiques National protocol [E5]. The LGS determines which genetic panels are used for genetic diagnosis [E1b], and therefore remains central to the diagnostic process in DRDs. Thus, validated approaches and tools provided by UEU in the fields of genetics and OCT have resulted in a paradigm shift in the diagnostic workup and outcomes for DRDs. The LGS and genetic testing are essential parts of the diagnostic workflow that forms the basis of clinical practice across specialist paediatric nystagmus services in the UK [E3, E6].

Using hand-held OCT, researchers at the University of Leicester have been able to demonstrate that the LGS predicts vision later in life for young pre-verbal infants [R6, G6]. This can be particularly worrying for parents as these children are not able to communicate the extent of their vision. Knowledge of future vision can allay the anxiety of parents of children with nystagmus. One parent has commented: “The OCT was essential in helping us to get a better understanding of what our daughter’s visual impairment meant for her … I can't imagine how I would be feeling without that assurance and information the OCT was able to yield!” [E7]. This very early diagnosis can make a huge difference to the outcomes for these children, who can be directed towards low vision resources, such as educational support, much earlier. This gives the best chance to support their developmental and educational achievements. Early diagnosis can also aid clinical decision-making and treatment planning.

Raising awareness and impact on clinical practice

Information generated from research into the impact of DRDs on quality of life and vision in daily life, was fed back directly to individuals with DRDs through patient-led conferences. Research from UEU has formed the basis of talks to people with DRDs on vision in daily life and on mental wellbeing. Joe Ambrico, the Vice President and research liaison for the American Nystagmus network has commented: “The American Nystagmus Network and its members are grateful for the continued support you have provided by sharing the results of your research at ANN events ... your research tends to focus on very practical matters that are of great interest to our members” [E8].

The expertise developed by the UEU has led to the development of Leicester as a referral point and centre of excellence for the management, diagnosis and treatment of DRDs and the clinic sees >600 patients with nystagmus per year, as well as neuro-ophthalmic and childhood eye diseases [E9].

Leicester is also an important centre for education in DRDs and high-resolution imaging of the retina, running international courses and training clinical staff since 2015. Gottlob and team have trained >100 clinicians at the Leicester Royal Infirmary Hospital and at Birmingham Children’s Hospital in the use of their improved hand-held OCT scanning methodology and LGS [E10].

Interest in this approach is extending globally, in September 2020, a live clinical symposium on clinical applications of hand-held OCT was attended by participants from 82 countries from Asia-Pacific, European Union, Latin-American, North East European, Middle East, African and North American regions.