Functional analysis of germline VANGL2 variants using rescue assays of vangl2 knockout zebrafish.

Developmental studies have shown that the evolutionarily conserved Wnt Planar Cell Polarity (PCP) pathway is essential for the development of a diverse range of tissues and organs including the brain, spinal cord, heart and sensory organs, as well as establishment of the left-right body axis. Germline mutations in the highly conserved PCP gene VANGL2 in humans have only been associated with central nervous system malformations, and functional testing to understand variant impact has not been performed. Here we report three new families with missense variants in VANGL2 associated with heterotaxy and congenital heart disease p.(Arg169His), non-syndromic hearing loss p.(Glu465Ala) and congenital heart disease with brain defects p.(Arg135Trp). To test the in vivo impact of these and previously described variants, we have established clinically-relevant assays using mRNA rescue of the vangl2 mutant zebrafish. We show that all variants disrupt Vangl2 function, although to different extents and depending on the developmental process. We also begin to identify that different VANGL2 missense variants may be haploinsufficient and discuss evidence in support of pathogenicity. Together, this study demonstrates that zebrafish present a suitable pipeline to investigate variants of unknown significance and suggests new avenues for investigation of the different developmental contexts of VANGL2 function that are clinically meaningful.

Participatory design of an infographic to help support the care of people living with complex regional pain syndrome.

Background: Complex regional pain syndrome (CRPS) can be a debilitating pain condition with enduring physical, psychological and social impacts. CRPS is often poorly understood by healthcare professionals and management needs to be tailored to each individual's presentation. People with lived experience express difficulty in accessing reliable and meaningful information about the condition. This study aimed to co-create a trustworthy infographic to share information about the lived experience of CRPS. Methods: We adopted a seven-phase, iterative, participatory methodology to co-create the infographic. Potential infographic content was obtained from qualitative work investigating the lived experience of CRPS. Online consumer engagement (people with doctor diagnosed CRPS/their family, n=20) was used to prioritise content to be included in the infographic and then potential designs were sourced. The research team narrowed the selections down to two designs which were presented to consumers online for final selection (n=25) and refinement (n=34). Results: An infographic for understanding the lived experience of CRPS was completed using participatory design, providing a resource aligned to the needs of people with this condition. Using the Patient Education Materials Assessment Tool, the final infographic rated highly for understandability (92%) and participants indicated significant willingness to share this infographic with others (93%). Conclusion: A process of participatory design was an effective and efficient process for translation of evidence gathered from qualitative research into a trustworthy resource for people with CRPS and their support people.