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.

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.

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.