Orphanet Journal of Rare Diseases | Long-term follow-up study of phenotypic variability in aortic disease among families with TGFBR2 gene variants

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This study followed a large French family spanning four generations with a pathogenic TGFBR2 variant, revealing significant phenotypic heterogeneity in aortic events and highlighting the importance of early diagnosis and prophylactic surgery in improving prognosis.

 

Literature Overview

The article titled 'Aneurysms of the ascending aorta are usually asymptomatic but potentially fatal due to the risk of aortic dissection' published in Orphanet Journal of Rare Diseases, reviews and summarizes the occurrence of aortic events in family members carrying pathogenic TGFBR2 variants. Based on longitudinal clinical data collected from 1990 to 2024, the study analyzed 63 family members with the same TGFBR2 variant, focusing on changes in the incidence of aortic dissection and prophylactic surgery, as well as survival and phenotypic differences across generations. The study also noted that despite carrying the same genetic variant, clinical manifestations varied significantly, suggesting the influence of modifier genes or environmental factors. This article provides important insights into phenotypic variability in aortic diseases related to the TGF-β signaling pathway.

Background Knowledge

Aortic diseases, particularly ascending aortic aneurysms and dissections, are potentially life-threatening cardiovascular conditions commonly associated with hereditary connective tissue disorders such as Marfan syndrome and Loeys-Dietz syndrome. The TGFBR2 gene encodes the transforming growth factor-beta receptor 2 (TGFBR2), and its pathogenic variants are closely linked to aortic dilation and dissection. While previous studies have indicated that TGFBR2 variants can lead to variable phenotypes, the significant intrafamilial variability remains unexplained, suggesting possible involvement of phenotypic modifier genes or environmental factors. Currently, aortic root surgery is the main treatment, but with surgical advancements, valve-sparing procedures are gradually replacing mechanical replacements. Additionally, gender differences in aortic events have shown inconsistencies with previous literature, indicating possible unique population characteristics. Therefore, a deeper investigation into phenotypic variability within families harboring TGFBR2 variants is crucial for understanding the genetic and environmental mechanisms of aortic diseases and for guiding personalized therapeutic strategies.

 

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Study Methods and Experimental Design

The study included 151 family members, of which 63 were confirmed carriers of the TGFBR2 pathogenic variant (Q508Q). Clinical data were collected from 1990 to 2024, including information on aortic dissection, surgical interventions, causes of death, and measurements of aortic diameter. The Fine-Gray model was used to analyze the risk of first events, and cumulative incidence curves were generated using the Aalen-Johansen estimator. Statistical analyses were performed using the survival package in R.

Key Findings and Observations

• Among the 63 carriers of the TGFBR2 variant, 21 (33%) died, 10 (48%) of whom died from aortic dissection.
• Eight patients (13%) underwent prophylactic aortic root surgery, and surgical approaches shifted from mechanical Bentall procedures to valve-sparing techniques.
• Over successive generations, the incidence of aortic dissection significantly decreased (p < 0.001), and life expectancy increased (p < 0.001), but there was no significant change in the composite endpoint (surgery, dissection, or death) (p = 0.168).
• Despite carrying the same variant, there was significant variability in the age of onset and severity of aortic events among individuals, suggesting the influence of modifier genes or environmental factors.
• Skeletal evaluations revealed that some carriers had no skeletal abnormalities, while others exhibited Marfan-like phenotypes, further supporting phenotypic heterogeneity.
• The gender ratio (male:female) of aortic events was 1:1, which contradicts the previously reported higher incidence in males.

Significance and Future Directions

This study highlights the high phenotypic heterogeneity among individuals carrying the same TGFBR2 pathogenic variant, suggesting that family history and environmental factors should be integrated into genetic counseling and risk assessment. The shift in surgical approaches reflects advances in clinical management. Future studies could combine whole-genome sequencing and epigenetic analysis to explore the role of modifier genes or epigenetic regulation in phenotypic variability. Additionally, environmental factors such as hypertension, smoking, and physical activity levels may influence disease expression and warrant further investigation.

 

Variant Analysis Tool (Variant): Annotate and filter gene variants discovered through sequencing to narrow down candidate variants, suitable for in-depth analysis of TGFBR2 variants.

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Conclusion

By tracking a large French family with a TGFBR2 pathogenic variant across four generations, this study revealed significant phenotypic variability in aortic disease manifestations even among individuals sharing the same genetic mutation. It emphasized the importance of early diagnosis and prophylactic surgery in improving survival outcomes and suggested that future research should explore how modifier genes and environmental factors influence phenotypic expression. These findings provide valuable insights for genetic counseling, clinical management, and mechanistic studies of TGF-β pathway-related diseases.

 

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.