Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy.

Aortopathy can be defined as aortic dilation, aneurysm, dissection, and tortuosity. Familial aortopathy may occur secondary to fibrillin-1 (FBN1) mutations in the setting of Marfan syndrome, or may occur as a result of other genetic defects with different, but occasionally overlapping, phenotypes. Because of the phenotypic overlap and genetic heterogeneity of disorders featuring aortopathy, we developed a next generation sequencing (NGS) assay and comparative genomic hybridization (CGH) array to detect mutations in 10 genes that cause thoracic aortic aneurysms (TAAs). Here, we report on the clinical and molecular findings in 175 individuals submitted for aortopathy panel testing at ARUP laboratories. Ten genes associated with heritable aortopathies were targeted using hybridization capture prior to sequencing. NGS results were analyzed, and variants were confirmed using Sanger sequencing. Array CGH was used to detect copy-number variation. Of 175 individuals, 18 had a pathogenic mutation and 32 had a variant of uncertain significance (VUS). Most pathogenic mutations (72%) were identified in FBN1. A novel large SMAD3 duplication and FBN1 deletion were identified. Over half who had TAAs or other aortic involvement tested negative for a mutation, suggesting that additional aortopathy genes exist. We anticipate that the clinical sensitivity of at least 10.3% will rise with VUS reclassification and as additional genes are identified and included in the panel. The aortopathy NGS panel aids in the timely molecular diagnosis of individuals with disorders featuring aortopathy and guides proper treatment.

The impact of bridge-to-transplant ventricular assist device support on survival after cardiac transplantation.

OBJECTIVE: To determine the impact of bridge-to-transplant ventricular assist device support on survival after cardiac transplantation. METHODS: From January 1, 1993, to April 30, 2009, a total of 525 cardiac transplants were performed. Ventricular assist devices were placed as a bridge to transplant in 110 patients. We focused our analysis on the 2 most common causes of end-stage heart failure requiring transplantation: idiopathic dilated cardiomyopathy (n = 201) and coronary artery disease (n = 213). Data including gender, age, date of transplant, cause of heart failure, prior heart transplant, placement of a ventricular assist device, type of ventricular assist device, and panel-reactive antibody sensitization were analyzed to derive Kaplan-Meier survival probabilities and multivariable Cox regression models. RESULTS: In patients with idiopathic dilated cardiomyopathy who received a ventricular assist device as a bridge to transplant, survival was decreased at 1 year (P = .008) and 5 years (P = .019), but not at 10 years, posttransplant. In patients with coronary artery disease, the use of a ventricular assist device as a bridge to transplant did not influence survival at 1, 5, and 10 tears posttransplant. In patients with idiopathic dilated cardiomyopathy who received a Heartmate I (Thoratec Corp, Pleasanton, Calif) ventricular assist device as a bridge to a cardiac transplant, elevation in the pretransplant panel-reactive antibody correlated with a decrease in long-term survival. CONCLUSION: In patients with idiopathic dilated cardiomyopathy, placement of a Heartmate I ventricular assist device as a bridge to a cardiac transplant is associated with an elevation in the pretransplant panel-reactive antibody and a decrease in 1- and 5-year survivals after cardiac transplantation.