In a large cohort of 373 pediatric patients with Marfan syndrome (MFS) with a severe cardiovascular phenotype, we explored the proportion of patients with MFS with a pathogenic FBN1 variant and analyzed whether the type/location of FBN1 variants was associated with specific clinical characteristics and response to treatment. Patients were recruited on the basis of the following criteria: aortic root z-score > 3, age 6 months to 25 years, no prior or planned surgery, and aortic root diameter < 5 cm. Methods: Targeted resequencing and deletion/duplication testing of FBN1 and related genes were performed. Results: We identified (likely) pathogenic FBN1 variants in 91% of patients. Ectopia lentis was more frequent in patients with dominant-negative (DN) variants (61%) than in those with haploinsufficient variants (27%). For DN FBN1 variants, the prevalence of ectopia lentis was highest in the N-terminal region (84%) and lowest in the C-terminal region (17%). The association with a more severe cardiovascular phenotype was not restricted to DN variants in the neonatal FBN1 region (exon 25-33) but was also seen in the variants in exons 26 to 49. No difference in the therapeutic response was detected between genotypes. Conclusion: Important novel genotype-phenotype associations involving both cardiovascular and extra-cardiovascular manifestations were identified, and existing ones were confirmed. These findings have implications for prognostic counseling of families with MFS.
Marfan syndrome and related disorders are a group of heritable connective tissue disorders and share many clinical features that involve cardiovascular, skeletal, craniofacial, ocular, and cutaneous abnormalities. The majority of affected individuals have aortopathies associated with early mortality and morbidity. Implementation of targeted gene panel next-generation sequencing in these individuals is a powerful tool to obtain a genetic diagnosis. Here, we report on clinical and genetic spectrum of 53 families from India with a total of 83 patients who had a clinical diagnosis suggestive of Marfan syndrome or related disorders. We obtained a molecular diagnosis in 45/53 (85%) index patients, in which 36/53 (68%) had rare variants in FBN1 (Marfan syndrome; 63 patients in total), seven (13.3%) in TGFBR1/TGFBR2 (Loeys–Dietz syndrome; nine patients in total) and two patients (3.7%) in SKI (Shprintzen–Goldberg syndrome). 21 of 41 rare variants (51.2%) were novel. We did not detect a disease-associated variant in 8 (15%) index patients, and none of them met the Ghent Marfan diagnostic criteria. We found the homozygous FBN1 variant p.(Arg954His) in a boy with typical features of Marfan syndrome. Our study is the first reporting on the spectrum of variants in FBN1, TGFBR1, TGFBR2, and SKI in Indian individuals.
Thoracic aortic aneurysm and dissection (TAAD) is a major cause of cardiovascular morbidity and mortality. Loss-of-function variants in LOX, encoding the extracellular matrix crosslinking enzyme lysyl oxidase, have been reported to cause familial TAAD. Using a next-generation TAAD gene panel, we identified five additional probands carrying LOX variants, including two missense variants affecting highly conserved amino acids in the LOX catalytic domain and three truncating variants. Connective tissue manifestations are apparent in a substantial fraction of the variant carriers. Some LOX variant carriers presented with TAAD early in life, while others had normal aortic diameters at an advanced age. Finally, we identified the first patient with spontaneous coronary artery dissection carrying a LOX variant. In conclusion, our data demonstrate that loss-of-function LOX variants cause a spectrum of aortic and arterial aneurysmal disease, often combined with connective tissue findings.
<p>Global change is a growing problem, governed by demographic, economic and climatological drivers. Such developments are leading to an increasing demand for natural resources. Traditionally, management of products and services from water, energy, and food sectors has been addressed with a sectoral policy approach (siloes) or through thematic modeling within individual sectors. However, this led to neglecting potential impacts of policy or resource changes in one sector on other sectors. A novel way to address this complexity is the nexus approach, which attempts to identify synergies and trade-offs between sectors. The water-energy-food (WEF) nexus approach offers opportunities to consider holistic policy integration and the nexus-wide impacts of adopted policies on physical interactions. In addition to the traditional WEF sectors, we believe that the climate and land sector are also of particular importance, because of their large potential influence on water, energy and food.</p><p>Consequently, in the present study, we adopted a multi-centric nexus approach to systematically investigate synergies, conflicts and trade-offs between the five nexus sectors of water, land, energy, food and climate in Sweden, that emerge both in interactions between physical resources and between different policy goals. This was done by combining a policy coherence analysis and system dynamics modelling. The policy analysis enabled us to identify key nexus-relevant policies, assess the coherence between them, and reveal the most important synergies and conflicts, while the system dynamics modelling allowed for the exploration of the physical interactions in this complex system. We here present the results of this extensive analysis, which was based on expert judgement, literature reviews, quantitative modelling and multi-stakeholder engagement at all stages of the project. The value of multi-stakeholder involvement is highlighted, and critical lessons learned for exploring nexus interactions are presented.</p>
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