Clinical Interpretation of Genetic Variants in the Evaluation and Management of Thoracic Aortic Aneurysm and Dissection.

BACKGROUND: We aimed to elucidate clinical implications of genetic variant interpretation in assessing disease severity and progression in thoracic aortic aneurysm and dissection (TAAD) patients. METHODS: Consecutive TAAD patients with aortic root and/or ascending aortic aneurysms seen between 2011 and 2020 were included. Serial echocardiography, family history of TAAD, and management information were retrospectively collected and analyzed. Patients were classified into gene-positive (Gen-P), variants of uncertain significance, and gene-negative (Gen-N) groups. RESULTS: A total of 407 patients were included: mean age 53.7±15.4 years, 64.4% women, and 38% with reported family history of TAAD. Thirty-seven (9.1%) were Gen-P; 147 (36.1%) had a variant of uncertain significance. Maximal aneurysm diameter was 4.78 mm larger in Gen-P than the other groups (P=.0003). In 162 unoperated TAAD patients with serial echocardiographic measurements, aneurysms enlarged at a significantly higher rate in the Gen-P (1.36 mm/year, 95% CI: 0.77-1.95) than variants of uncertain significance and Gen-N groups (0.83 mm/year vs 0.89 mm/year, respectively; P<.001). Aneurysms were 20% more likely to require surgical intervention for every millimeter increase in diameter. When considered on an individual basis, the highest growth rates were found in the variants of uncertain significance group. CONCLUSION: While aneurysms linked to variants of uncertain significance demonstrate average growth rates comparable to those in Gen-N, close follow-up and genetic counseling in the variants of uncertain significance group are recommended for assessment of pathogenicity on a case-by-case basis. Early familial gene testing in TAAD is important to develop individualized preventive and therapeutic criteria.

Kinetics of 99Tc speciation in aerobic soils.

Technetium-99 is a significant and long-lived component of spent nuclear fuel relevant to long-term assessments of radioactive waste disposal. Whilst 99Tc behaviour in poorly aerated environments is well known, the long-term bioavailability in aerobic soils following direct deposition or transport to the surface is less well understood. This work addresses two questions: (i) to what extent do soil properties control 99Tc kinetics in aerobic soils and (ii) over what experimental timescales must 99Tc kinetics be measured to make reliable long-term predictions of impact in the terrestrial environment? Soil microcosms spiked with 99TcO4- were incubated for 2.5 years and 99Tc transformations were periodically monitored by a sequential extraction, which enabled quantification of the reaction kinetics. Reduction in soluble 99Tc was slow and followed a double exponential kinetic model including a fast component enhanced by low pH, a slow component controlled by pH and organic matter, and a persistently soluble 99Tc fraction. Complexation with soil humus was key to the progressive immobilisation of 99Tc. Evidence for slow transfer to an unidentified 'sink' was found, with estimated decadal timeframes. Our data suggest that short-term experiments may not reliably predict long-term 99Tc solubility in soils with low to moderate organic matter contents.

Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage.

Over 1,500 gene mutations are known to cause hypertrophic cardiomyopathy (HCM). Previous studies suggest that cardiac ß-myosin heavy chain (MYH7) gene mutations are commonly associated with a more severe phenotype, compared to cardiac myosin binding protein-C (MYBPC3) gene mutations with milder phenotype, incomplete penetrance and later age of onset. Compound mutations can worsen the phenotype. This study aimed to validate these comparative differences in a large cohort of individuals and families with HCM. We performed genome-phenome correlation among 80 symptomatic HCM patients, 35 asymptomatic carriers and 35 non-carriers, using an 18-gene clinical diagnostic HCM panel. A total of 125 mutations were identified in 14 genes. MYBPC3 and MYH7 mutations contributed to 50.0% and 24.4% of the HCM patients, respectively, suggesting that MYBPC3 mutations were the most frequent cause of HCM in our cohort. Double mutations were found in only nine HCM patients (7.8%) who were phenotypically indistinguishable from single-mutation carriers. Comparisons of clinical parameters of MYBPC3 and MYH7 mutants were not statistically significant, but asymptomatic carriers had high left ventricular ejection fraction and diastolic dysfunction when compared to non-carriers. The presence of double mutations increases the risk for symptomatic HCM with no change in severity, as determined in this study subset. The pathologic effects of MYBPC3 and MYH7 were found to be independent of gene mutation location. Furthermore, HCM pathology is independent of protein domain disruption in both MYBPC3 and MYH7. These data provide evidence that MYBPC3 mutations constitute the preeminent cause of HCM and that they are phenotypically indistinguishable from HCM caused by MYH7 mutations.