December 2022 - Research Update from Professor Nicky Ragge and her research team
To all the families participating in the Genetics of Eye Anomalies Research, and those interested, here is a summary of our key achievements in 2022.
Welcome to our first newsletter to participating families from Professor Nicola Ragge’s research team. Throughout 2022 many families have indicated that they would like to receive updates on the progress of the Genetics of Eye Anomalies Study, so we have put together some of 2022’s most exciting developments here.
Contents:
- The Genetics of Eye Anomalies Study
- Expansion of the team and research findings published in 2022o
- Solving a 20-year mystery: why every family counts in eye research
- Investigating the range of symptoms associated with the geneFZD5
- The Optical Genome Mapping Project using the Bionano Genomics Saphyr System
- The GoOD Meeting, Toulouse, France, May 2023
The Study
The Genetics of Eye Anomalies Study first began in 1999 at Moorfields Eye Hospital and currently continues through Birmingham Women’s and Children’s Hospital Foundation Trust, Oxford Hospitals and Oxford Brookes University, where the laboratory research team is based. Over 420 families are taking part in the study and to date we have fed back a genetic finding that helps to explain the basis to our family’s eye condition to approximately27%, with some families awaiting confirmation in NHS labs. For the remaining 73% of families we are striving to search for an answer, using the most advanced scientific methods available including Whole Genome Sequencing and now Optical Genome Mapping, which you can read more about in this newsletter.
In recent years our team and other research groups have identified many genes involved in eye development. We are advising Genomics England, the body overseeing NHS genetic testing in England, on the genes that should be included in diagnostic genetic testing for developmental eye conditions. As of November 2022 the test panel includes 125 genes underlying anophthalmia, microphthalmia, coloboma, anterior segment conditions and developmental glaucoma.
Expansion of the team and research findings published in 2022
2022 saw the expansion of the research group in order to embark on the Optical Genome Mapping study. A second Research Coordinator, Dr Fiona Watkins joined Dr Dorine Bax to coordinate aspects of the team's research and liaise with the families taking part. Dr Solomon Merepa and Ms Karthika Jeganathan joined as Post-Doctoral Research Assistant and Research Assistant respectively. They join Senior Research Fellow Dr Richard Holt, focussing on the optical genome mapping studies, Dr Lidiya Talbot on bioinformatics, Dr Hande Tunbak on zebrafish studies and visiting researchers, Dr Fabiola Ceronion whole genome and exome sequencing and copy number variant analysis and Dr Sam Clokie on bioinformatics. The team look forward to welcoming visiting researcher Dr Bertrand Chesneau from Toulouse in January 2023.
We would like to highlight two important papers the group have published recently:
“Analysis of Fibroblast Growth Factor 14 (FGF14) structural variants reveals the genetic basis of the early onset nystagmus locus NYS4 and variable ataxia”.Ceroni et al., published in the European Journal of Human Genetics, October 7th2022.
Solving a 20-year mystery: why every family count in eye research
The process of identifying the genetic cause of an individual’s eye disorder can be lengthy because of the limitations of the technology available at the time and also as certain combinations of clinical feature sare incredibly rare. A recent example of this is our work on the geneFGF14, which has allowed us to finally solve a mystery spanning nearly 20 years. In 1993 we identified a family with a very distinctive form of nystagmus (involuntary, rhythmical eye movements or ‘unsteady eyes’).The technology available at the start of the new millennium allowed us to pin point the genetic cause to a region on chromosome 13 which contained several genes, but then the trail went cold. However, fast-forward 17 years and we were contacted by a doctor who had read about our work and was treating a family with an extremely similar eye disorder. His work had identified a genetic change toFGF14, but he was uncertain of its significance. AsFGF14was located within the critical region identified in our original family, we reassessed the family with a new technique. This enabled us to discover that the affected family members were all missing part of the samegene,FGF14. Together, this allowed us to confirm the importance of a change in FGF14in causing this distinctive form of nystagmus in both families. Importantly, the work also highlighted the need for clinics to look for changes inFGF14in children with nystagmus. This is a good example of how the participation of every family is valuable in research and makes it possible for researchers to expand the knowledge and understanding of developmental eye conditions which in turn can lead to new treatments. “Individuals with heterozygous variants in the Wnt-signalling pathway gene FZD5 delineate a phenotype characterized by isolated coloboma and variable expressivity”. Holt et al.2022.Accepted for publication in the Special Issue of ‘Ophthalmic Genetics’ in memory of A. Linn Murphree, Professor of Ophthalmology, first Division Chief of Paediatric Ophthalmology and Director of the Retinoblastoma Program at Children’s Hospital Los Angeles and the University of Southern California.
Investigating the range of symptoms associated with the gene FZD5
Sometimes a person with anophthalmia, microphthalmia or coloboma (AMC) has an alteration in a gene which contributes to their disorder, but this genetic change is also present in an apparently unaffected member of their family. Moreover, some people with changes in a gene may only have symptoms affecting their eyes, while others with changes in the same gene may have additional disorders affecting other areas of the body. Part of our research is to understand why this happens.
One gene for which both these statements are trueisFrizzled-5(orFZD5for short), which causes colobomas and more rarely microphthalmia, with the condition limited to the eyes. We teamed up with groups in the UK, France and Spain to identify eight new families with AMC and changes toFZD5;as expected in several cases these alterations were inherited from parents with apparently normal eyes. However, after a very detailed examination of the parents, we discovered that several had extremely mild colobomas at the back of the eye; so mild, in fact, that their vision was unaffected and the findings had previously gone undetected. Furthermore, although there were some patients with FZD5 gene changes who had conditions affecting other parts of the body these individuals had changes in other genes that would explain these additional features. Therefore, we are recommending that apparently unaffected family members who have a genetic alteration to FZD5are re-examine for mild colobomas that could have previously been missed. Furthermore, if the patient has disorders in addition to AMC, we suggest clinics look for changes in other genes which will help to explain these disorders. Together, this will enable clinicians to discuss with their patients the possible developmental eye conditions which might be experienced by their children, should they inherit a change in this gene.
The team have recently submitted three further papers on other research findings for publication in high profile scientific journals; we look forward to their publication in early 2023and will provide an update for you later in the year.
Optical Genome Mapping Project with the Bionano Genomics Saphyr System
After a successful drive to collect new blood samples from families recruited to the study, we have prepared special high molecular weight DNA ready for testing. This DNA is fluorescently labelled and a microscopic detailed map of the genetic make-up (chromosomes) of each individual determined using the Bionano Genomics Saphyr System. Optical Genome Mapping (OGM)enables researchers to look for small regions of DNA that are missing, additional, or in the wrong place and then investigate the significance of any variant found. OGM is a very sensitive technique and we are hopeful that it will enable us to detect changes in DNA in some families which have been missed by traditional sequencing techniques.
Genetics of Ocular Development Society annual meeting 2023
We are looking forward to the fourth annual GoOD (Genetics of Ocular Development) meeting in Toulouse, France in May 2023. This meeting will bring together geneticists, ophthalmologists and scientists worldwide to share ideas for the diagnosis of genetic eye conditions, an understanding of these conditions and their development and to determine therapeutic strategies. This is an excellent opportunity for professionals in the field to meet, discuss their findings and collaborate on future projects. How to contact the study team The research coordinators for the study always like to hear from families–both those already taking part, or others who might be interested in joining our study. If you have any questions, or would like an update on testing you are most welcome to contact the team by email (eye.genetics.study@brookes.ac.uk) or telephone 01865 483913 (Fiona) or 01865 484413 (Dorine). Professor Ragge is continuing to accept referrals for NHS Genetics Consultation and testing through Birmingham Women’s and Children’s NHS Foundation Hospital Trust; if you are interested in this, the research coordinators can give you information on how to arrange this.
Lastly, a huge thank you to our sponsors, in particular Baillie Gifford, Edinburgh, Scotland and MACS, and all our donors and to the families who have contributed to the research. Without your help we cannot make the important advances that will improve the lives of families worldwide with eye conditions.
January 2022 - Research Update from Professor Nicky Ragge and her research team
Dear MACS families,
Happy New Year! We hope you are keeping well in these challenging times. We wanted to take this opportunity to update you on our research and the exciting projects we have underway.
First, we warmly congratulate the new Chair of MACS - Naomi Bowman. We look forward to working closely together in the next coming months and years.
Professor Ragge’s research and our progress in identifying new genes and diagnoses for families would not be possible without the ongoing participation of many MACS families recruited in our study. It’s wonderful that over 450 families are now part of our study, some of whom joined us many years ago. Thank you all for your continued support.
Our research team in Oxford is led by Professor Nicky Ragge, who was awarded a personal Chair dedicated to researching the Genetics of Eye Anomalies – the Baillie Gifford Professorship of Developmental Eye Genetics. Co-ordinating the research is Dr Dorine Bax, and there are four dedicated senior Researchers plus one visiting Researcher all undertaking different aspects of the research: Dr Richard Holt, Dr Yesim Kesim, Dr Lidiya Talbot, Hande Tunbak and Dr Fabiola Ceroni. Our team continues to expand to support the growing research areas and we are currently recruiting a second Research Co-ordinator and another senior Researcher, who will undertake new projects. We work closely with the West Midlands Regional Genetics Lab, the largest genetics lab in the country, and the Oxford Genetics Lab on analysing the results for the Structural Eye Disease gene panel and collaborate closely with twelve centres from around the world.
We continue to offer state of the art techniques to families to test for the genetic causes of structural eye disorders, such as MAC conditions, linking with the NHS testing that we have helped to develop through our national eye genomics centre and Genomics England. Currently, we use techniques that test all the genes (whole genome and whole exome sequencing) to map the genetic code and identify genes that may be altered, and our research team is working hard analysing our latest batches of data. These techniques have already provided the answers to several of our families.
We are very excited to share with you that we shall be implementing a new technique called optical gene mapping (using BioNano technology); this examines genetic changes, which may go undetected using whole genome or exome sequencing, and are too small to detect using microarrays (detailed chromosome testing). This new method has the potential to reach a genetic diagnosis where earlier tests have been unable to do so.
Since 2019 we have been privileged to host and help organise annual global scientific meetings on genetic eye disease- the Genetics of Ocular Development (GoOD) meetings. These meetings have been paramount in uniting expert scientists and clinicians from across the world to discuss diagnosis, clinical aspects, and future strategies in terms of therapeutics. Through this network, we have established strong collaborations with international clinical and research centres, vital for sharing expertise on the molecular diagnosis of MAC conditions so families can receive optimal care and counselling, adopting the best practices from around the world. Representatives from MACS have attended these meetings and are welcome to do so in the future. We have established a new international society, called the Genetics of Ocular Development (GoOD) Network, which is led by Professor Ragge with her two colleagues Professor Patrick Calvas and Dr Nicolas Chassaing from Toulouse, France and collaborating with close colleagues based around the world.
We continue to work closely with diagnostic laboratories within the NHS where our research results are confirmed and genetic diagnoses made, and fed back to families. Professor Ragge has played a key role in developing and continuously updating the diagnostic gene panel R36 Structural Eye Disease, which is a list of genes used by Genomics England in NHS gene testing to diagnose MAC and other structural eye disorders. We also continue to identify new genes. As a recent example, using whole exome sequencing (testing all the genes) in a family with microphthalmia and coloboma, we identified a change in a gene (CAPN15), which at the time was not linked to MAC conditions. International collaborations with groups in Canada and Saudi Arabia helped to find other families where the same gene was affected, and further evidence from model organisms supported the role of CAPN15 in MAC. This research was published in a top academic journal and as a result, this gene is now routinely tested on the NHS in families with MAC conditions.
We also wanted to update you on some exciting developments within NHS genetic diagnostic services. Through the NHS Genomic Medicine Service, whole genome sequencing is now available for MAC and other structural eye conditions using the R36 Structural Eye Disease gene panel. This means that any Specialist (usually a Consultant Clinical Geneticist or Genetic Ophthalmologist) can request whole genome sequencing as a diagnostic test for MAC families through one of the three centres: Central and South (Wessex, West Midlands, Oxford, Southampton), North West (Manchester, North East and Yorkshire, East), North Thames (London and South East) and this panel of genes would be analysed. Detailed informed consent for whole genome sequencing is now discussed with trained teams, a process that is more detailed than previous genetic testing consents.
It is also important to mention that although whole genome sequencing testing reads the sequence of all the genes we have, only 114 genes are actually analysed (the ones that fall into the R36 Structural Eye Disease gene panel), not all the genes. Being recruited into a research setting that investigates the genetics of eye structural disorders (including MAC), such as the study of the Genetics of Eye and Brain anomalies, led by Professor Ragge, means that other genes can be analysed and that diagnostic and research testing are linked from the start. Thereby, further testing can be undertaken via research if the NHS testing is unable to identify the underlying genetic diagnosis and uncertain findings can be analysed in further depth using research capabilities, which are outside the scope of the NHS.
Lastly, Professor Ragge is expanding her NHS clinics: from February alongside virtual/telephone appointments and her in-person clinics in Rugby and at the Institute of Translational Medicine (ITM), Birmingham, she will hold paediatric clinics at the Rare Disease Centre, located at the Birmingham Children’s Hospital in central Birmingham (which is just a walk away from Birmingham New Street and Snow Hill Stations). Families can be referred via their GP, ophthalmologist, paediatrician or geneticist. Families can be recruited to the research from these clinics, if they wish.
For more information on how to get involved in Professor Ragge’s research, please contact Dorine Bax at dbax@brookes.ac.uk or on 01865 484413.
If you want to know more about our research, please visit: https://www.brookes.ac.uk/research/units/hls/groups/molecular-genetics-of-human-eye-development/
If you want to know more about the GoOD meetings, please visit: https://www.goodsoc.org/meetings/2019
We will be organising virtual meetings for families to update you on recent research developments from our own research and others. All MACS families are welcome regardless whether you are participating in our study. If you would like to receive more information, please contact Dorine Bax.