Orphanet Journal of Rare Diseases | Clinical Phenotype Study of Aortic Events in TGFBR2 Mutation Families

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The study, through long-term follow-up of 63 individuals across four generations carrying pathogenic TGFBR2 variants, reveals that the same mutation can lead to a wide range of phenotypic variability from asymptomatic to severe aortic dissection. It also demonstrates that with advances in diagnostic and surgical techniques, the incidence of aortic dissection has decreased and survival has improved within the family.

 

Literature Summary
This article, titled 'A large French family with TGFBR2 pathogenic variant: illustration of variability', published in the journal Orphanet Journal of Rare Diseases, reviews and summarizes the occurrence of aortic events and their clinical phenotypic heterogeneity in a large French family with pathogenic TGFBR2 variants. The article presents longitudinal clinical data from 1990 to 2024, showing significant differences in the severity and age of onset of aortic disease among family members despite carrying the same mutation.

Background
Aortic diseases are a group of rare diseases with high genetic heterogeneity, and pathogenic variants in the TGFBR2 gene represent one of the main genetic causes of Loeys-Dietz syndrome. The gene encodes the transforming growth factor β receptor 2, and its mutations can affect vascular development, smooth muscle function, and the TGF-β signaling pathway, leading to aortic aneurysms and dissections. Although numerous studies have explored the relationship between TGFBR2 mutations and aortic disease, the mechanisms underlying phenotypic variability remain incompletely understood. This study, based on a large French family with the Q508Q mutation in TGFBR2, further explores phenotypic expression across generations and the impact of surgical interventions and diagnostic advances on disease progression. It provides important clinical evidence for understanding phenotypic variability in TGFBR2-related aortic diseases and lays the foundation for future genotype-phenotype correlation studies and personalized intervention strategies.

 

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Study Design and Methods
From 1990 to 2024, researchers conducted a longitudinal clinical study on a large French family with a pathogenic TGFBR2 variant, including 63 mutation carriers across four generations. The study evaluated the incidence of aortic events, including dissection and prophylactic surgery, and their changes over time. All clinical data were obtained from the National Referral Center for Marfan Syndrome and supplemented by interviews with treating physicians. Fine-Gray models were used to handle competing risks, and cumulative incidence curves were generated using Aalen-Johansen estimators. The study also assessed aortic diameter, skeletal phenotypes, and other extra-cardiovascular features.

Key Findings and Observations

• Among the 63 family members carrying pathogenic TGFBR2 variants, 21 (33%) passed away, with 10 (48%) of those deaths caused by aortic dissection.
• 8 patients (13%) underwent prophylactic aortic root surgery, with surgical approaches transitioning from mechanical valve replacement to valve-sparing procedures.
• The incidence of aortic dissection decreased across generations (p < 0.001), and overall survival improved, although the composite endpoint of aortic events (surgery, dissection, or death) did not show significant change (p = 0.168).
• Significant variability in aortic disease manifestations was observed among individuals with the same TGFBR2 variant. The youngest patient with dissection was a 17-year-old female, while the oldest unaffected individual was an 80-year-old female.
• There was no significant difference in the incidence of aortic events between males and females (1:1), which contrasts with the male predominance reported in previous literature.
• Skeletal abnormalities were common, but no severe extra-cardiovascular manifestations such as pneumothorax or craniosynostosis were observed.
• The study suggests that phenotypic variability may be influenced by modifier genes, differences in transcript isoform expression, or environmental factors such as hypertension and smoking.

Implications and Future Directions
This study highlights significant clinical variability in aortic disease among individuals sharing the same pathogenic mutation, suggesting the need to further explore the roles of modifier genes and environmental influences. Future studies may focus on functional differences among TGFBR2 transcript isoforms and the application of personalized medical strategies in mutation carriers. Additionally, the decline in aortic dissection incidence over time underscores the importance of early screening and prophylactic interventions in improving patient outcomes.

 

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Conclusion
This study, through long-term follow-up of a large French family with a pathogenic TGFBR2 variant, reveals that a single mutation can result in a wide phenotypic spectrum ranging from asymptomatic to early-onset aortic dissection. It also shows that with advances in diagnostics and surgical techniques, the incidence of aortic dissection has decreased and survival has improved, although the overall disease progression remains largely unchanged. These findings emphasize the importance of systematic screening among mutation carriers and suggest that phenotypic variability may be influenced by modifier genes or environmental factors. Furthermore, the study provides valuable insights into the mechanisms and potential intervention strategies for TGFBR2-related diseases, particularly in optimizing genotype-phenotype correlations in rare aortic disorders.

 

Ludivine Eliahou, Olivier Milleron, Skerdi Haviari, Catherine Boileau, and Guillaume Jondeau. A large French family with TGFBR2 pathogenic variant: illustration of variability. Orphanet Journal of Rare Diseases.