VEDS Research: Variances of Uncertain Significance (VUS)

VEDS Research: VUS

Elucidating functional significance of ‘Variants of Uncertain Significance’ by generating and characterising a zebrafish model for Vascular Ehlers-Danlos Syndrome.

31 May 2024: Annabelle’s Challenge Vascular EDS Charity announces £50,000.00 grant for new scientific vEDS research project.

We're delighted to have reaffirmed our objective to enabling research in vascular EDS (vEDS) by awarding a £50,000.00 grant to a University of Sheffield research project ‘Elucidating functional significance of ‘Variants of Uncertain Significance’ by generating and characterising a zebrafish model for Vascular Ehlers-Danlos Syndrome.’

This project aims to investigate the genetic alterations found in patients with vascular Ehlers -Danlos syndrome (vEDS). These alterations are officially termed Variants of Uncertain Significance (VUS), as there is currently insufficient information regarding their likelihood of causing disease (pathogenic) or not.

Although the genetic heterogeneity present in Vascular Ehlers-Danlos Syndrome is well understood, the pathways linking genetic alterations and the various variants of uncertain significance to the disease phenotype remain obscure.

The primary objective is to identify and reclassify the VUS most prevalent in patients according to the criteria set forth by the Association for Clinical Genomic Science (ACGS) and the American College of Medical Genetics and Genomics (ACMG). VUS that remain significant will undergo functional studies using zebrafish, a small fish widely used in scientific research. Employing advanced techniques, the Balasubramanian group will edit the fish genome, generating a zebrafish model with mutations in the genes responsible for collagen production, like the patients with vEDS. Subsequently, they will analyse how close to vascular EDS this zebrafish model is so it provides a way into using zebrafish as a disease model to further clarify the significance of these VUS.

In addition to these functional studies, this animal model will also be suitable for drug screening and potentially for future gene therapy research.

The work is being overseen by Dr Meena Balasubramanian who is an academic clinical geneticist based in Sheffield. She has recently taken over the role of Clinical Director of Research at Sheffield Children’s Hospital.

The project is due to commence in January 2025 and is made possible thanks to donations received in memory of Rob Reyner.

Meena Balasubramanian, PI on this project said, “I am really grateful to Annabelle’s challenge for supporting this really exciting and worthwhile project on exploring VUS in vascular EDS which is a growing problem with advanced genetic testing and using zebrafish as a model to understand the underlying cause of vEDS.”

Jared Griffin, Founder & CEO “This is an exciting project and a turning point for the charity as we fund scientific research for vascular EDS. Variants of uncertain significance is a very important area of work and I am delighted this is now being researched through the University of Sheffield with Dr Balasubramanian leading the project.”

Lead Researcher

Dr Meena Balasubramanian is an academic clinical geneticist based in Sheffield. She has recently taken over the role of Clinical Director of Research at Sheffield Children’s Hospital.

Her research is focused on genetics of Osteogenesis Imperfecta (OI) and genotype-phenotype correlation in newly identified genes. She is currently pursuing an MRC Fellowship, having established her own lab on zebrafish disease models for bone fragility. She has published over 120 principal-author publications and textbooks including a recent molecular medicine series on OI. She has also edited and written several patient information leaflets on rare genetic disorders for Unique (www.rarechromo.org) and Brittle Bone Society.

Meena is a leading researcher into several rare neurodevelopmental disorders (RNDD) genes and runs natural history studies, including, HNRNPU and ASXL3. Meena’s group have published the largest clinical cohorts for the following rare neurodevelopmental disorder (RNDD) genes: HNRNPU, ASXL3, SIN3A, IQSEC2, YWHAG, ZMYND11 and written the expert literature reviews (Genereview/ Orphanet) for ASXL3, HNRNPU & SIN3A.

Her other roles include Clinical Director of Research at Sheffield Children’s Hospital; Research Director, North East and Yorkshire NHS Genomic Medicine Service Alliance. She is Secretary for Clinical Genetics Society and serves on the ‘Medical Advisory Board’ for Brittle Bone Society, HNRNP Family Foundation and Chair of the ‘Sheffield Advanced Therapeutics- Development and Delivery Collaborative’ at Sheffield Children’s Hospital.

Why use Zebrafish?

The zebrafish (Danio rerio) is a model organism widely used in biological research. It is a fresh water fish, part of the Cyprinids family in the ray-finned fish class.

Zebrafish and human genomes share around 70% homology. Moreover, 82% of morbidity-associated genes in human have been linked to at least one ortholog in the zebrafish. These similarities support the relevance of the model, but the advantages of zebrafish are also practical.

First, the zebrafish is a small organism and requires less infrastructure and nursing than mammalian models such as rodents. Their generation time is longer, approximately three to four months compared to 1.5 months for mice, but the descendants are far more numerous, with hundreds of eggs by clutch spawn every two or three days.

Rob Reyner Research Funding

Funding for this research project is granted from a donation of £50,000.00 in memory of Rob Reyner.

Rob joined Annabelle's Challenge in May 2017 and attended the world’s first ever vascular EDS Conference held during the same month at The Village Hotel, Bury. He was a keen advocate of our work to help others affected by vascular EDS despite his own suffering and the loss of his father and brother to the same condition.

Rob was one of our main supporters hosting his annual Eurovision party to raise awareness and funds for REDS4VEDS and Annabelle's Challenge. He would have attended our second Conference on 14th May 2022 however it clashed with his Eurovision 2022 party, sadly he passed away the same day.

Over the past eight years' Rob and his family and friends have donated a significant amount of funds for Annabelle’s Challenge. Rob’s legacy continues ensuring his wishes are fulfilled benefiting the wider vEDS community in the future.