Sexual dimorphism in SMAD3 pathogenic variant-harbouring individuals

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.