Active BRIDGE Studies - EDS

Prof. Timothy J. Aitman

Prof. Timothy J. Aitman

This study will investigate the genetic basis of rare inherited connective tissue conditions, mainly the Ehlers-Danlos syndromes (EDS) and those with overlapping phenotypes, which includes familial thoracic aortic aneurysm/dissection (TAAD).

These are diseases, which share a generalised connective tissue weakness (connective tissue collectively describes the elements which keep the structures of the body together). These can mainly lead to the symptoms of Ehlers-Danlos syndrome, including: vascular fragility (predisposing an individual to aneurysm and rupture of blood vessels), hypermobility (loose-jointedness), hyper-extensible skin and other effects. Furthermore, a similar mechanism is thought to underlie a significant familial predisposition to aneurysm/dissection of the thoracic aorta. These conditions often present at a young age and are associated with premature mortality.

We do not currently have a full understanding of which genes are responsible in the various types of EDS or familial TAAD and approximately 70-80% of patients remain undiagnosed, even after sequencing the known causative genes. Therefore, there is a considerable gap in our knowledge of the underlying genetic cause and mechanisms leading to these rare but severe diseases.

Currently we are working with the National EDS diagnostic service in London as well as a number of other centres of excellence for EDS and TAAD, from which we are recruiting cases as follows: National Ehlers-Danlos syndrome diagnostic service, Northwick Park Hospital, London (PI: Prof F.M. Pope / Dr. A. Vandersteen), Department of Rheumatology Hypermobility service, UCLH (PI: Prof R. Grahame / Dr. H. Kazkaz), Vascular Unit, Imperial College Healthcare NHS Trust (PI: Prof N. Cheshire), Cardiac surgery unit, Royal Brompton & Harefield NHS Trust (PI: Prof J. Pepper); Liverpool Heart & Chest Hospital (PI: Mr M. Field).

Whole exome sequencing will help to identify hitherto undiscovered genes underlying EDS and familial TAAD, thereby providing insight into the molecular pathways underlying these conditions. There will be a direct translational benefit to patients and their relatives by providing a number of undiagnosed individuals with a specific molecular diagnosis, leading to preventative family screening, risk-stratification and prognostication. Molecular genetic characterisation would complement the current clinical classification and treatment of EDS, which is limited, and, for TAAD provide novel insights into disease prognosis, upon which surgical management hinges.