Identification of novel splice mutation in SMAD3 in two Cypriot families with nonsyndromic thoracic aortic aneurysm. Two case reports

Abstract Background Thoracic aortic aneurysm and dissection (TAA/D) represents a potentially lethal disease group characterized by an increased risk of dissection or rupture. Only a small percentage (approximately 30%) of individuals with nonsyndromic familial TAA/D have a pathogenic variant in one of the genes that have been found to be associated with the disease. Methods A targeted sequencing panel and direct sequencing approach were used to identify causative mutations in the index patients and other family members. Results In this study we report two apparently unrelated Cypriot families with nonsyndromic familial TAA/D. The proband A is a female patient diagnosed with TAA/D and intracranial aneurysm and opted for an elective intervention. The proband B is a male patient who was diagnosed with TAA/D and underwent cardiac surgery. Sequencing analysis identified a novel splice site variant (c.871+1G>A) in SMAD3 which is shown to be associated with the disease. Analysis of mRNA from the patient's tissue confirmed aberrant splicing and exon 6 skipping. Conclusion Our findings expand the mutation spectrum of variants that have been shown to be associated with nonsyndromic familial TAA/D. This study demonstrates the importance of a comprehensive clinical and genetic evaluation aiming at early diagnosis and intervention

Baroclinic Torque and Implications for Subgrid-Scale Modeling

Baroclinic torque plays an important role in the dynamics of variable-density flows. Large eddy simulations using Favre-filtered resolved-scale velocities mask the explicit dependence of resolved-scale dynamics on subgrid-scale pressure-gradient-density interactions. The effect of subgrid-scale baroclinic torque on resolved scales is implicitly included in the subgrid-scale stress and subgrid-scale scalar fluxes through the resolved-scale vorticity it generates. LES closure models must therefore incorporate this effect in the computations. We explore the physics of subgrid-scale baroclinic torque within the structural framework of the Stretched-Vortex model. Fine-scale simulations of supersonic flows and direct numerical simulations of variable-density turbulence are investigated. Such flows have regions of active baroclinic torque and serve to set up flow configurations to assess the model