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PHD Defence: Functional characterization of potential ciliary genes involved in syndromic inherited retinal diseases

22/6/2020

 
Giulia Ascari virtually defended her PhD thesis on June 18 2020. Congratulations to our doctor, whose favorite genes are RCBTB1 & CEP78.

PHD DEFENCE: Disclosing incidental and secondary findings in clinical genomics: professional practice, patient experience and ethical reflection

11/5/2020

 
On the 27th of April 2020, Marlies Saelaert virtually defended her PhD thesis. This was an unforgettable experience. Congratulations!

PhD defence: Communication through the eyes of the patient: the role of ethnicity, language and education

11/5/2020

 
Our new team member, Karolien Aelbrecht, virtually defended successfully her PhD thesis on April 28 2020. Well done, congratulations Karolien!

new paper out: Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics

27/4/2020

 
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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

17/4/2020

 
Check out our latest paper in Proceedings of the National Academy of Sciences of the United States of America. You can read the abstract below, for the full text click here.

The interplay of transcription factors and cis-regulatory elements (CREs) orchestrates the dynamic and diverse genetic programs that assemble the human central nervous system (CNS) during development and maintain its function throughout life. Genetic variation within CREs plays a central role in phenotypic variation in complex traits including the risk of developing disease. We took advantage of the retina, a well-characterized region of the CNS known to be affected by pathogenic variants in CREs, to establish a roadmap for characterizing regulatory variation in the human CNS. This comprehensive analysis of tissue-specific regulatory elements, transcription factor binding, and gene expression programs in three regions of the human visual system (retina, macula, and retinal pigment epithelium/choroid) reveals features of regulatory element evolution that shape tissue-specific gene expression programs and defines regulatory elements with the potential to contribute to Mendelian and complex disorders of human vision.
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Article in the physicians' paper

15/4/2020

 
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.

Elfride De Baere is Visionary of the Quarter

15/4/2020

 
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.

ERN-EYE Interview of the Month: Elfride De Baere

15/4/2020

 
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

14/4/2020

 
Check out our latest paper in Clinical Genetics. You can read the abstract below, for the full text click here.

Biallelic MFSD8 variants are an established cause of severe late-infantile subtype of neuronal ceroid lipofuscinosis (v-LINCL), a severe lysosomal storage disorder, but have also been associated with nonsyndromic adult-onset maculopathy. Here, we functionally characterized two novel MFSD8 variants found in a child with juvenile isolated maculopathy, in order to establish a refined prognosis. ABCA4 locus resequencing was followed by the analysis of other inherited retinal disease genes by whole exome sequencing (WES). Minigene assays and cDNA sequencing were used to assess the effect of a novel MFSD8 splice variant. MFSD8 expression was quantified with qPCR and overexpression studies were analyzed by immunoblotting. Transmission electron microscopy (TEM) was performed on a skin biopsy and ophthalmological and neurological re-examinations were conducted. WES revealed two novel MFSD8 variants: c.[590del];[439+3A>C] p.[Gly197Valfs*2];[Ile67Glufs*3]. Characterization of the c.439+3A>C variant via splice assays showed exon-skipping (p.Ile67Glufs*3), while overexpression studies of the corresponding protein indicated expression of a truncated polypeptide. In addition, a significantly reduced MFSD8 RNA expression was noted in patient's lymphocytes. TEM of a skin biopsy revealed typical v-LINCL lipopigment inclusions while neurological imaging of the proband displayed subtle cerebellar atrophy. Functional characterization demonstrated the pathogenicity of two novel MFSD8 variants, found in a child with an initial diagnosis of juvenile isolated maculopathy but likely evolving to v-LINCL with a protracted disease course. Our study allowed a refined neurological prognosis in the proband and expands the natural history of MFSD8-associated disease.
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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

14/4/2020

 
Check out our latest paper in Scientific Reports. You can read the abstract below, for the full text click here.

This study aimed to genetically and clinically characterize a unique cohort of 25 individuals from 21 unrelated families with autosomal recessive nanophthalmos (NNO) and posterior microphthalmia (MCOP) from different ethnicities. An ophthalmological assessment in all families was followed by targeted MFRP and PRSS56 testing in 20 families and whole-genome sequencing in one family. Three families underwent homozygosity mapping using SNP arrays. Eight distinct MFRP mutations were found in 10/21 families (47.6%), five of which are novel including a deletion spanning the 5' untranslated region and the first coding part of exon 1. Most cases harbored homozygous mutations (8/10), while a compound heterozygous and a monoallelic genotype were identified in the remaining ones (2/10). Six distinct PRSS56 mutations were found in 9/21 (42.9%) families, three of which are novel. Similarly, homozygous mutations were found in all but one, leaving 2/21 families (9.5%) without a molecular diagnosis. Clinically, all patients had reduced visual acuity, hyperopia, short axial length and crowded optic discs. Retinitis pigmentosa was observed in 5/10 (50%) of the MFRP group, papillomacular folds in 12/19 (63.2%) of MCOP and in 3/6 (50%) of NNO cases. A considerable phenotypic variability was observed, with no clear genotype-phenotype correlations. Overall, our study represents the largest NNO and MCOP cohort reported to date and provides a genetic diagnosis in 19/21 families (90.5%), including the first MFRP genomic rearrangement, offering opportunities for gene-based therapies in MFRP-associated disease. Finally, our study underscores the importance of sequence and copy number analysis of the MFRP and PRSS56 genes in MCOP and NNO.
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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

14/4/2020

 
Check out our latest paper in Human Mutation. You can read the abstract below, for the full text click here.

Inactivating variants in the centrosomal CEP78 gene have been found in cone-rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state-in trans with c.1462-1G>T-in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggest impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities
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Best oral presentation @ BeSHG 2020

14/4/2020

 
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!

Prize Foundation John W. Mouton KBS

14/4/2020

 
Introduction
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.

Scientific abstract
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.

Lay summary
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

14/4/2020

 
At the end of 2019, Sarah Naessens succesfully defended her PhD thesis on "Recurrent coding and rare non-coding targets for treatment in inherited retinal diseases". Congratulations Sarah and good luck with your future challenges!

RARE-MED: Precision medicine in rare diseases

1/10/2019

 
ResearchUGent started off the RARE-MED consortium on precision medicine for rare diseases with 3 new research professors Sarah Vergult, Kris Vleminckx & Frauke Coppieters. Looking forward to addressing missing heritability, modeling disease, and introducing new gene therapies!

RARE-MED is a multidisciplinary consortium for basic and translational research on precision medicine for rare diseases, to address missing heritability using systems genetics and functional genomics, to facilitate disease modelling using CRISPR/Cas9-mediated genome editing of aquatic model organisms (zebrafish, Xenopus) and of cellular systems, to introduce new gene therapies based on antisense oligonucleotide- or CRISPR/Cas9-based genome editing. RARE-MED will bring UGent in a unique strategic position as an international reference center for rare disease
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