new paper out: Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement
PHD Defence: Functional characterization of potential ciliary genes involved in syndromic inherited retinal diseases
PHD DEFENCE: Disclosing incidental and secondary findings in clinical genomics: professional practice, patient experience and ethical reflection
PhD defense: Communication through the eyes of the patient: the role of ethnicity, language and education
new paper out: Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics
In a recently published manuscript in the prestigious journal Genetics in Medicine, a large group of collaborators, led by dr. Claire-Marie Dhaenens and prof. Frans Cremers in the Department of Human Genetics in Nijmegen, the Netherlands, identified the causal mutations in the ABCA4 gene in 448 individuals with Stargardt disease (STGD1). They employed a cost-effective method, based on so-called smMIPs, to sequence the complete ABCA4 gene consisting of 128,313 base pairs. Through a semi-automated procedure, they tested more than 1,000 probands with STGD1 and allied maculopathies for the presence of causal mutations (Khan et al. Genet Med, in press).
Remarkably, they found 105 causal mutations residing in the introns of the ABCA4 gene that led to the disruptive insertion of these non-coding sequences in the messenger RNA and thus a non-functional ABCA4 protein. Among 13 novel RNA insertions identified in splicing assays, they found two intriguing complex RNA defects due to variants in introns 13 and 44. In addition, they found 16 novel large deletions, two of which were complex. Altogether, these ‘hidden mutations’ were found in 27% of the 448 genetically solved cases, illustrating the unusually high proportion of these types of mutations in STGD1.
This study was made possible through the collaboration of 75 scientists and clinicians from 21 countries from all over the world. Due to the low sequencing costs (€ 30,- per case), the research team in Nijmegen now offers this test to any individual with STGD1 or allied maculopathy in the world, at no costs, on a research basis.
This work was made possible through several grants, the most significant of which were from the RetinaUK, Fighting Blindness Ireland, Foundation Fighting Blindness USA, and the EU.
New paper out: Mapping the cis-regulatory Architecture of the Human Retina Reveals Noncoding Genetic Variation in Disease
The John W. Mouton Pro Retina grant that was awarded to prof. Elfride De Baere for her research project Precision medicine in inherited blindness using integrated omics in patient-derived stem cell models was mentioned in the physicians' paper. To read the article click here.
Prof. De Baere was chosen as the Visionary for the first quarter of 2020 by vision-research.eu. To read more about her work on precision medicine to understand missing heritability in inherited retinal diseases, you can click here.
Every month, ERN-EYE invites you to meet an active person within the network through a short interview. This month, it's prof. Elfride de Baere who accepted to answer their questions. You can read the entire interview here or watch the video below.
New paper out: Functional Characterization of Novel MFSD8 Pathogenic Variants Anticipates Neurological Involvement in Juvenile Isolated Maculopathy
New paper out: The Majority of Autosomal Recessive Nanophthalmos and Posterior Microphthalmia Can Be Attributed to Biallelic Sequence and Structural Variants in MFRP and PRSS56
New paper out: Functional Characterization of the First Missense Variant in CEP78, a Founder Allele Associated With Cone-Rod Dystrophy, Hearing Loss, and Reduced Male Fertility
The 20th BeSHG meeting "Genome for all?" was held in Brussels on the 6th of March, 2020. We are very proud that Stijn won best oral presentation for his talk "Whole genome sequencing and 4C techniques provide novel insights into the genetic architecture and mechanisms underlying North Carolina macular dystrophy, a cis-regulatory disease". Congratulations Stijn!
Every two years, the Fund John W. Mouton Pro Retina (managed by the King Baudouin Foundation) awards a grant of € 30.000 to a researcher working at a university or research center in Europe that is pursuing medical scientific research in the field of the pathologies of the retina. The fund is interested in all kind of retinal diseases (genetic, diabetic, hypertensive, post-prematurity, degenerative, toxic retinopathy, etc.) with exception of retinal tumors. The work may concern clinical research as well as basic research including a concrete perspective on further clinical work. In 2019, the John W. Mouton Pro Retina grant was awarded to prof. Elfride De Baere for her research project Precision medicine in inherited blindness using integrated omics in patient-derived stem cell models.
Inherited retinal disease (IRD) is a major cause of early-onset blindness affecting 2 million people worldwide. Significant advances have been made in the genomic underpinnings of IRD, which has culminated in novel therapies entering the clinic. Despite this progress, there are important knowledge gaps that hamper a molecular diagnosis in over half of the cases.
We and others have shown a role for non-coding variation in undiagnosed IRD and demonstrated these are novel targets for therapy. Here, it is our main goal to accelerate diagnosis in unsolved IRD and to uncover novel targets for intervention. First, we will generate human cellular models of undiagnosed monoallelic patients with suspected recessive IRD. Second, we will establish an integrated omics framework to accelerate diagnosis in unsolved IRD. Third, we will translate research findings to the clinic through ERN-EYE and patient advocacy organizations.
Our multidisciplinary approach involves ophthalmic genetics/genomics, (functional) genomics, bioinformatics, transcriptomics, proteomics, statistical genomics, and stem cell technology. Our expertise combined with a strong track record and international network offer a unique opportunity to address unmet needs and to pave the way to precision medicine in IRD.
Inherited retinal diseases represents major cause of certifiable blindness in the working age and childhood population. Despite a revolution in DNA technology that allowed to find genetic causes in half of the cases and that has culminated in successful gene therapies, essential knowledge is lacking to establish a genetic diagnosis in the remaining half of the patients, representing about 175.000 people in Europe.
With this project we aim to improve the discovery of hidden mutations in inherited retinal disease, often residing in the ‘dark matter’ of the genome, and to find novel targets for intervention. From blood cells of patients with undiagnosed inherited retinal diseases we will make stem cells that we will let develop to cells that mimic light-sensitive retina cells (photoreceptors) that express disease-causing genes of interest. We will perform large-scale DNA, RNA, and protein studies on these cells from patients and controls. By integrating these three layers of information, we will develop a sophisticated strategy to pinpoint hidden mutations in undiagnosed patients. These mutations may represent novel targets for intervention studies. This proposal has expected health impact, accelerating a definite diagnosis in inherited retinal diseases, improving genetic counseling, reproductive options, disease prognosis and management and ultimately offering therapeutic opportunities. We will transfer results from our study to the patients through our local clinical and international networks.
PhD Defence: Recurrent coding and rare non-coding targets for treatment in inherited retinal diseases