Prof. Frans Cremers
Professor Cremers is leading a Fighting Blindness and HRB joint-funded project exploring macular disease-associated genes and risk factors.
Project: High-throughput sequencing of inherited and multifactorial macula disease-associated genes and risk factors allows identification of genetic interactions and modifiers.
Start date: 2021
Award amount: €300,000 with Fighting Blindness contributing €150,000 to the project and HRB contributing €150,000.
Frans Cremers is a Professor of Ophthalmogenetics in the Department of Human Genetics in the Radboudumc in Nijmegen.
The project is in collaboration with Professor Jane Farrar based in Trinity College Dublin. Both Prof Cremers and Prof Farrar’s team members contribute to the project, in particular Dr. Rebekkah Hitti-Malin, postdoc, Nijmegen, and Ms. Ella Kopcic, PhD candidate, Dublin.
We spoke to Professor Frans Cremers, Dr. Rebekkah Hitti-Malin (postdoc, Nijmegen), and Ms. Ella Kopcic, (PhD candidate, Dublin). Find out more about the project below.
2. Why did you get into research and what do you most enjoy about it?
3. Within the next five years, where do you expect great advances to be made in vision research?
4. What are your other interests?
5. More detailed information on the project.
1. What are the overall aims of the project you are working on, including how it could have an impact on those affected by sight loss?
The project is looking at macular diseases in more detail. In the retina is not functioning correctly and thus affected persons experience difficulties with their central vision. Inherited macular diseases which can occur at an early age, are relatively rare and typically result in several decades of vision impairment. The more common age-related macular degeneration (AMD) generally affects older people.
Although great progress has been made in identifying the underlying genetic factors for macular diseases, we still lack knowledge regarding genetic and non-genetic factors that influence the age at onset and severity of macular diseases. As part of this collaborative study funded by Fighting Blindness, we aimed to develop a cost-effective method to sequence regions of genes that are involved in providing the instructions to make proteins (termed the coding regions of genes). The coding regions of genes associated with inherited and age-related macular disease were sequenced.
Detailed sequence analysis of 1,352 individuals with a suspected inherited macular disease led to the identification of candidate causative mutations in 49 different genes in 509 individuals. We identified known and new variants that had not been previously implicated in forms of macular disease before, which can shed light on new molecular mechanisms for disease. Ultimately, knowledge of disease-causing mutations gives patients a genetic diagnosis, and may offer potential options for therapies for these individuals.
In the next year we will perform a comparison of the occurrence of genetic risk variants in cases with inherited macular disease versus cases with age-related macular disease cases, as we hypothesize that some genetic risk variants could be involved in both cohorts.
These studies should significantly increase the ability to diagnose macular disease cases which should identify individuals who may be eligible for novel therapies, and where appropriate, may aid people to make lifestyle and dietary changes, thereby improving long-term vision prospects. These studies will bring together an extensive network of clinical collaborators, scientists and patient groups to address this important group of diseases. – Prof. Frans Cremers
2. Why did you get into research and what do you most enjoy about it?
Dr. Rebekkah Hitti-Malin, postdoc, Nijmegen:
My PhD focused on identifying genetic variants causing inherited blindness in dogs. My interest in hunting for a causal mutation and understanding the genetics of inherited retinal disorders encouraged me to seek opportunities in the field of human retinal research.
I enjoy the sense of discovery when identifying genetic defects underlying disease, and to make a meaningful difference to the lives of patients suffering with these devastating conditions. It is a pleasure to be able to collaborate with others in this field to impact patient care and help provide patients with an understanding to their disease. – Dr. Rebekkah Hitti-Malin
Ms. Ella Kopcic, PhD candidate, Dublin:
I completed my undergraduate degree in Jane Farrar’s lab while working on a Stargardt disease research project, a form of retinal degeneration. It was during that time that I realized the rapid growth in our knowledge of human genetics, its direct application to eye disease and that I would like to pursue a career in vision research. I was able to see first-hand the sort of impact that this research can have on patients, and I knew I wanted to get involved in any way I could.
This particular research project was extremely interesting to me because it feels like we are solving extremely important puzzles, and at times even like building cases as a detective to identify the likely causes of the disease in patients. The more we can find out, the more complete the genetic diagnosis is for patients, and this is most definitely the most exciting aspect of my work. – Ms. Ella Kopcic
3. Within the next five years, where do you expect great advances to be made in vision research?
Based on a Nijmegen blindness genetics team roundtable discussion, we believe that these advances will be made in the next 5 years:
- Whole genome and RNA sequencing of blood cells will enter the diagnostic routine
- Long-read whole genome sequencing for inherited retinal diseases will be done before the patient meets the ophthalmologist or clinical geneticist (so-called ‘gene-first’ approach)
4. What are your other interests?
Dr. Rebekkah Hitti-Malin, postdoc, Nijmegen:
As an English-woman living in the Netherlands, I have a keen interest in learning to speak Dutch! I like to practice these language skills by reading Dutch (children’s!) books to learn new words and phrases. I am also creative and in my spare time I like to make jewellery using silversmithing techniques.
Ms. Ella Kopcic, PhD candidate, Dublin:
I enjoy reading emerging studies in macular research, and other areas of human genetics. I also have a keen interest in marine life studies, with a particular focus on sharks and reef rescue, among others. Outside of work I would mainly focus on reading fiction, enjoying movies and immersing myself in other worlds.
5. More detailed information on the project.
As part of this collaborative study funded by Fighting Blindness, we aimed to develop a cost-effective method to sequence regions of genes that are involved in providing the instructions to make proteins, termed the coding regions of genes. The coding regions of genes associated with inherited and age-related macular disease (MDs) were sequenced. We used a rapid and cost-effective method for DNA sequencing using so-called ‘Single Molecule Molecular Inversion Probes’ (smMIPs).
More than 17,000 of these smMIPs were designed covering approximately 450,000 DNA building blocks, targeting the protein-coding regions of all 105 genes associated with MDs, 89 age-related MD-associated risk factor variants, and the mitochondrial DNA. The mitochondrial DNA is the part of the DNA that is particularly involved in generating components to sustain cellular energy supplies. As a result, 1,831 inherited MD, 1,123 age-related MD (AMD) and 847 non-AMD individuals have been sequenced using this MD-smMIPs approach (Hitti-Malin et al, 2022, PMID 36259723; Hitti-Malin et al., in preparation).
Professor Cremers has previously received funding from Fighting Blindness. Learn more about that project here