Abstract Background Aneurysms of the ascending aorta are usually asymptomatic but potentially fatal due to the risk of aortic dissection. Some aneurysms are genetic in origin (autosomal dominant transmission), and family screening can improve the prognosis of these patients. In patients with pathogenic variants of the TGFBR2 gene, there is a considerable clinical variability. Manifestations can vary from aggressive aneurysms with early dissection to late-onset non-syndromic aneurysms or asymptomatic carriers. The variability is also observed within a given family carrying the same TGFBR2 pathogenic variant, meaning that a particular variant may be associated with a more (or less) severe phenotype. The initial recognition of the role of the TGF-β pathway, and in particular TGFBR2 was made possible by linkage analysis in a large French family for which follow-up data are reported here. Purpose of this study is to report aortic events in a large family carrying the same variant in the TGFBR2 gene. Methods 63 members of the same family carrying the TGFBR2 variant (1524G→A; Q508Q) were followed for 4 generations since 1990. A family member was considered affected if he or she carried the familial pathogenic variant, regardless of clinical features, if he or she had an aortic event (prophylactic aortic root surgery or aortic dissection either type A or type B), and if they were obligate carriers, even if their genetic status was unknown. For statistical analysis, only the first event (aortic dissection or prophylactic aortic surgery) has been considered. Results As shown on the pedigree and flow chart (figure 1a and 1b), 21 patients died (33% of the population), of whom 10 were related to a dissection (48% %). 8 patients underwent prophylactic aortic root surgery (13%). Over the generations, there is an increase in life expectancy (figure 2a) and a decrease in the likelihood of aortic dissection (Figure 2b; p0.05), but no significant change in the combined endpoint of surgery, aortic dissection or death (p=0.2). In the latest generation, surgery was performed earlier (Figure 2c). The type of prophylactic surgery has also evolved over the years from mechanical Bentall surgery to valve-sparing surgery. Conclusion From these results, we can observe the evolution of patient care and the type of surgery since the increase in life expectancy and the reduction in the likelihood of aortic dissections. The combined endpoint including prophylactic aortic surgery, aortic dissection or death does not vary significantly, consistent with the fact that prophylactic aortic surgery prevents aortic dissection and death but does not alter the course of aortic disease, which remains stable across generations. The heterogeneity in the age of onset of aortic events illustrates the variability of aortic disease associated with this variant. Figure 1) a: Pedigree of the family, including only affected members. b: Aortic event risk flow chart Figure 2) Survival curves.
Eliahou et al. (Sat,) studied this question.