Key result
Females with SMAD3 variants show ~37% higher non-penetrance for vascular involvement compared to males.
Why the study?
Based on prior reports of sex differences in thoracic aortic aneurysm or dissection, the authors investigated sexual dimorphism for vascular events in SMAD3 pathogenic variant-harbouring patients.
Are there sex differences in the penetrance and localization of vascular events among individuals harboring SMAD3 pathogenic variants?
Observational (n=220)
Are there sex differences in the penetrance and localization of vascular events among individuals harboring SMAD3 pathogenic variants?
Women with SMAD3 pathogenic variants exhibit higher non-penetrance for vascular events and more frequently have vascular involvement sparing the aortic root compared to men, indicating that normal echocardiography is less reassuring in at-risk females.
May reduce reassurance from normal echocardiography in females with SMAD3 variants; leaves open need for sex-specific risk models.
Background Individuals harbouring SMAD3 pathogenic variants are at risk for aneurysms/dissections throughout the arterial tree. Based on prior reports of sex differences in thoracic aortic aneurysm/dissection, we investigated the sexual dimorphism for vascular events in SMAD3- variant-harbouring patients. Methods We analysed two large pedigrees comprising 84 individuals segregating pathogenic missense variants affecting the same p.Arg287 residue in SMAD3 . We excluded individuals<40 years without vascular involvement, as they were too young to be classified. Individuals were subcategorised according to sex, the presence or absence and localisation (aneurysm/dissection with or without involvement of the aortic root/ascending aorta) of vascular lesions. We complemented our familial patient cohort with 178 SMAD3 patients reported in the literature between 2011 and 2023. Results In our two pedigrees, 11/30 (37%) variant-harbouring females had no vascular involvement, whereas none of the variant-harboring males (n=23) had no vascular involvement (p=0.001). While the two groups did not differ by age, males were at higher risk of vascular complications (p=0.037), there was no age difference between sexes. Of the 19 females with vascular involvement, six (32%) had vascular involvment sparing the aortic root/ascending aorta, whereas of the 23 males with vascular invovlement, only one (4%) had vascular involvement sparing the aortic root/ascending aorta (p=0.034). In the literature, we identified 116 male and 62 female additional patients. In the combined cohort of 220 patients, we demonstrated an over-representation of males (p<0.001) and non-penetrance in females for vascular pathology involving the aortic root/ascending aorta (p=0.028). Conclusions Non-penetrance is more common in women, and normal echocardiography in at-risk females is not as reassuring for risk of vasculopathy in other locations. The higher non-penetrance in women creates an ascertainment bias and results in an over-representation of male patients in the literature.
No takes yet. Share an insight, caveat, or question.
Richer et al. (2025) conducted an observational in SMAD3 pathogenic variants (n=220). Female sex vs. Male sex was evaluated on No vascular involvement (non-penetrance) (p=0.001). Among individuals with SMAD3 pathogenic variants, females had significantly higher rates of non-penetrance for vascular involvement compared to males (37% vs 0%, p=0.001).
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: