NEW PAPER ALERT!

By Alfredo Duenas Rey

​This study focuses on the significance of 5' untranslated region (5'UTR) variants in inherited retinal diseases (IRDs). It presents a comprehensive approach involving the analysis of retinal RNA data for 378 IRD genes, assessment of 5'UTR coverage in whole exome sequencing data, and evaluation of 5'UTR variants in large patient cohorts. The study identified 11 potentially pathogenic variants in 10 genes, with two of them validated as having functional effects. Notably, the MERTK:c.-125G>A variant reduced luciferase mRNA levels and activity, while the RDH12:c.-123C>T variant, found in conjunction with another reported variant, resulted in reduced RDH12 protein levels. This research underscores the importance of 5'UTR variants in IRDs and offers a systematic strategy for annotating and validating such variants, applicable to other inherited diseases.

NEW PAPER ALERT!

​By Dr. Eva D'haene & Victor Lopez Soriano

Through extensive comparative 3D genome mapping, based on genome-wide (Hi-C), promoter-centric (HiChIP) and locus-specific (UMI-4C) assays of human neural retina and RPE, we have shown that gene regulation at key IRD loci is likely mediated by tissue-specific chromatin interactions. These findings do not only provide insight into tissue-specific regulatory landscapes of IRD genes, but also delineate the search space for non-coding genomic variation underlying unsolved IRD.

GREAT NEWS!

ProgRET will create a multidisciplinary and intersectoral European training network focusing on the mechanisms, diagnosis and therapy of dominantly inherited retinal diseases (IRD). IRD represent a major cause of blindness, affecting 350,000 people in Europe. IRD have long been considered incurable, however major advances have led to groundbreaking new treatments. Today, the most important challenges in the IRD field relate to an unsolved genetic diagnosis, unknown disease mechanisms and gene therapy development for autosomal dominant IRD (adIRD), representing 25%–40% of all IRD cases. We have demonstrated an emerging role for splicing factors, structural variants and non-coding defects in patients with adIRD, and developed novel disease models and gene therapies for adIRD.
ProgRET aims to dissect adIRD mechanisms using retinal stem cell and aquatic animal models, to advance adIRD diagnostics using a single-molecule multi-omics framework, and to develop innovative treatments based on RNA therapy and CRISPR-genome editing. These challenges will be tackled by integrating unique expertise and cutting-edge technology within ProgRET, including (multi-)omics, bioinformatics, functional genomics, RNA biology, gene regulation, stem cell technology, retinal organoids, animal models, genome editing and gene therapy. ProgRET will give Doctoral Candidates (DCs) unparalleled training opportunities in outstanding academic and industrial settings through training-by-research via individual research projects, secondments, and network-wide training sessions. All individual training and research activities will provide each DC with the necessary skills in academic and industrial research. ProgRET will make a career in both sectors attractive and improve their career prospects. Finally, our multidisciplinary network offers a unique opportunity to accelerate the understanding, diagnostics and therapeutics for adIRD in Europe, and to translate research findings to healthcare and society.

Several Lab De Baere members made the trip to the States to attend ARVO 2022. Oral presentations were given by Munevver Burcu Cicekdal, Alfredo Dueñas Rey and Victor López Soriano, while Miriam Bauwens had a poster presentation.

Biomedical scientist and former master student Muhammad Rishfi (aka Affy) has been awarded the ‘Prijs Vrienden van de Bibliomedische Bibliotheek’ for the best interdisciplinary thesis with highest clinical relevance at the Faculty of Medicine and Health Sciences. So well deserved Affy!
What? ‘Gene and protein-based therapy of a dominant target in inherited retinal blindness’. Novel antisenseoligonucleotide & nanobody-based approach to target a dominant mutation in inherited blindness, specifically NR2E3 G56R.
Who? Despite COVID obstacles Affy did brilliant collaborative work with Sarah Naessens, Elfride De Baere, Jan Gettemans, Frauke Coppieters, Olivier Zwaenepoel & Steve Lefever. To be continued by team member Edith De Bruycker.

At the 21th BeSHG meeting "Reproductive Genetics", held in Brussels on September 17 2021, Stijn was awarded for his oral presentation titled "Dual molecular effects of dominant SF3B2 variants cause a novel spliceosomopathy displaying retinitis pigmentosa or developmental skeletal anomalies". This is the second year in a row Stijn has received an award  from the Belgian Society for Human Genetics. Congratulations Stijn!

Münevver Burcu Cicekdal received the poster prize at the 18th International Xenopus Conference for her work on rare human genetic disease for which she uses Xenopus tropicalis as a model organism. Congrats Burcu!

Check out our latest paper in Frontiers in Cell and Developmental Biology. This is a provisional acceptance at the moment. You can read the abstract below, for the full text click here.

Inactivating variants as well as a missense variant in the centrosomal CEP78 gene have been identified in autosomal recessive Cone-Rod Dystrophy with Hearing Loss (CRDHL), a rare syndromic inherited retinal disease distinct from Usher syndrome. Apart from this, a complex structural variant (SV) implicating CEP78 has been reported in CRDHL. Here we aimed to expand the genetic architecture of typical CRDHL by the identification of complex SVs of the CEP78 region and characterization of their underlying mechanisms. Approaches used for the identification of the SVs are shallow whole genome sequencing (sWGS) combined with quantitative PCR and long-range PCR, or ExomeDepth analysis on whole exome sequencing data. Targeted or whole genome nanopore long-read sequencing (LRS) was used to delineate breakpoint junctions at the nucleotide level. For all SVs cases, the effect of the SVs on CEP78 expression was assessed using qPCR on patient-derived RNA. Apart from two novel canonical CEP78 splice variants and a frameshifting single nucleotide variant, two SVs affecting CEP78 were identified in three unrelated individuals with CRDHL: a heterozygous total gene deletion of 235 kb and a partial gene deletion of 15 kb in a heterozygous and homozygous state, respectively. Assessment of the molecular consequences of the SVs on patient’s materials displayed a loss-of-function effect. Delineation and characterization of the 15 kb deletion using targeted LRS revealed the previously described complex CEP78 SV, suggestive for a recurrent genomic rearrangement. A founder haplotype was demonstrated for the latter SV in cases of Belgian and British origin, respectively. The novel 235 kb deletion was delineated using whole genome LRS. Breakpoint analysis showed microhomology and pointed to a replication-based underlying mechanism. Moreover, data mining of bulk and single-cell human and mouse transcriptional datasets, together with CEP78 immunostaining on human retina, linked the CEP78 expression domain with its phenotypic manifestations. Overall, this study supports that the CEP78 locus is prone to distinct SVs and that SV analysis should be considered in a genetic work-up of CRDHL. Finally, it demonstrated the power of sWGS and both targeted and whole genome LRS in identifying and characterizing complex SVs in patients with ocular diseases.

Dear RARE-MED colleagues and sponsors,

Everyone knows the unicorn, but no one has ever actually seen one. Unicorns only exist in a world of myth and fantasy. On the other hand, people with a rare disease do exist. And they are numerous… About 500,000 Belgians have a rare disease.
On the occasion of the International Day of Rare Diseases 2021 on February 28, we participate in the RadiOrg campaign “Not a Unicorn”. Because people with a rare disease are not unicorns. They really exist.
And you can help make them visible!
 
Sporty top athletes from UZ Gent and UGent will walk, run or cycle between 17 and 28 February 2021. They will be sponsored for this.
In addition to our ambassador of the Rare Diseases Fund, Frances Lefebure, our top RARE-MED team also puts on their sports shoes out of solidarity!
 
Would you like to sponsor our running, walking and cycling campaign?
Then choose this link!
Gifts from 40 € are tax deductible.
 
Thank you!!

Check out our latest paper in The American Journal of Human Genetics. You can read the abstract below, for the full text click here.

Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual. RIMS2 regulates synaptic membrane exocytosis. Data mining of human adult bulk and single-cell retinal transcriptional datasets revealed predominant expression in rod photoreceptors, and immunostaining demonstrated RIMS2 localization in the human retinal outer plexiform layer, Purkinje cells, and pancreatic islets. Additionally, nonsense variants were shown to result in truncated RIMS2 and decreased insulin secretion in mammalian cells. The identification of a syndromic stationary congenital IRD has a major impact on the differential diagnosis of syndromic congenital IRD, which has previously been exclusively linked with degenerative IRD.