Research heralds hope and PhD student Jessica Alvarez is busy in our laboratory, exploring the clinical and molecular consequences of variation in the FBN1 gene.
Over the past year, my research has focused on understanding the clinical and molecular consequences of variation in the FBN1 gene, which provides the instructions for making fibrillin-1, a protein that gives strength and elasicity to connective tissues throughout the body. This work spans ocular (eye) disease, hereditary aortopathy (inherited conditions affecting the aorta, the body's main artery) and severe early-onset Marfan syndrome.
At Queen Mary University of London, I’m working on hereditary thoracic aortic aneurysm and dissection (an inherited condition affecting the aorta) using whole-genome sequencing data from three families. I am integrating variant annotation (identifying and classifying genetic variants), inheritance patterns, population frequency, predicted functional impact and detailed phenotypic information (the clinical features seen in affected individuals) to prioritise candidate variants. Long-read sequencing evidence (a DNA sequencing technique that reads much longer stretches of DNA) is also being incorporated where available to clarify complex or previously uncertain findings. Attention is being given to genes and pathways involved in vascular smooth-muscle contraction (how the muscle cells in blood vessel walls function), extracellular-matrix integrity (maintaining the strength and structure of connective tissues), TGF-β signalling (a cell communication pathway important for growth, repair and connective tissue function), mechanotransduction (how cells sense and respond to physical forces) and RNA splicing (the process by which genetic instructions are edited before proteins are made).
For the Marfan Trust, I have been mapping FBN1 variants associated with neonatal and severe early-onset Marfan syndrome. This has involved curating and standardising variants from databases, published studies and clinical reports, then assessing their distribution across fibrillin-1 domains (different structural regions of the fibrillin-1 protein). I have also compared variants located within and outside the region traditionally associated with neonatal presentations. The aim is to test existing assumptions about genotype–phenotype correlations (how particular genetic changes relate to disease severity and clinical features), identify recurrent molecular patterns and support more accurate interpretation of severe early-onset cases. Structural assessment is additionally being used to explore how selected variants may disrupt calcium binding, disulfide bonding (chemical bonds that help stabilise proteins), protein folding (how a protein adopts its three-dimensional shape) and molecular interactions.
At the University College London Institute of Ophthalmology, I have been contributing to a research project examining the relationship between FBN1 variation and ocular manifestations (eye-related features of disease). This work involves reviewing current evidence on fibrillin-1 biology, extracellular-matrix organisation (the network of proteins that provides structure and support to cells and tissues) and the mechanisms through which pathogenic variants (disease-causing genetic changes) may affect ocular structures. The project also considers genotype–phenotype relationships (how specific genetic variants relate to the signs and severity of disease) and areas where further experimental and clinical research is needed.
Together, these projects combine genomic analysis (the study of a person's complete genetic information), literature synthesis (bringing together findings from published research) and structural interpretation to improve understanding of FBN1-related disease across different tissues and stages of presentation.
