Grant: Project Grant

Genetic diseases that affect connective tissues are associated with joint instability, pain, fractures and skeletal deformities, muscle weakness, and cardiovascular disease. Individuals with some such diseases, such as Marfan or Loeys-Dietz syndromes, experience catastrophic dissections and rupture of the aorta as well as other cardiovascular effects. For people with these diseases, early diagnosis, monitoring, and treatment including surgery are necessary for survival and quality of life. But these diseases are difficult to diagnose. Even when genetic diagnoses are available, it is difficult to predict need for surgery. This is because individuals vary in severity even for the same mutation. Better tools to diagnoses these diseases and predict disease severity are urgently needed. Our proposal addresses this gap in care by leveraging the fact that for many genetic diseases their various manifestations are often highly correlated. For heritable connective tissue disorders, this would mean that individuals with more severe connective tissue frailty may also have greater severity in features such as facial shape, stature, limb proportions or eye symptoms. We test this overall hypothesis in both human participants and animal models for heritable connective tissue disease as well as for mutations associated with risk of aortic rupture in humans. We will also determine whether the severity of risk for aortic dissection is associated with the severity of these other features among individuals who do not have a genetic diagnosis of a heritable thoracic aortopathy disorder. Our work is strongly grounded in prior research and preliminary data and embedded within collaborations and partnerships that will enable us to translate our findings into clinical practice. Although relatively few individuals are affected by these genetic diseases, their severe consequences mean that their care accounts for a significant portion of health care cost as well as burden of disease.