Related Experiment Video
Updated: Jun 4, 2025
Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information
Published on: August 15, 2019
Sexual dimorphism in SMAD3 pathogenic variant-harbouring individuals
Julie Richer1,2, Joe Davis Velchev3, Sharan Goobie4
1Department of Medical Genetics, Children's Hospital of Eastern Ontario Regional Genetics Program, Ottawa, Ontario, Canada juricher@cheo.on.ca.
Insights
Women with SMAD3 variants show higher rates of non-penetrance for vascular disease, meaning they are less likely to develop aneurysms or dissections compared to men. This difference in penetrance affects how we understand and diagnose vascular conditions in SMAD3-variant carriers.
Area of Science:
- Genetics and Cardiovascular Medicine
- Vascular Biology and Disease Mechanisms
Background:
- Pathogenic variants in SMAD3 are associated with a risk of aneurysms and dissections across the arterial tree.
- Previous studies suggest sex-based differences in thoracic aortic aneurysm and dissection, prompting investigation into SMAD3-related vascular events.
Purpose of the Study:
- To investigate the sexual dimorphism in vascular events among patients carrying pathogenic SMAD3 variants.
- To determine if there are sex-specific differences in the manifestation and location of vascular pathology in SMAD3-variant carriers.
Main Methods:
- Analysis of two large pedigrees (84 individuals) with pathogenic missense variants in SMAD3 affecting p.Arg287.
- Exclusion of individuals under 40 without vascular involvement; categorization by sex, vascular lesion presence/absence, and location (aortic root/ascending aorta involvement).
- Supplementation of familial cohort with 178 SMAD3 patients from literature (2011-2023) for a combined analysis.
Main Results:
- Females (37%) showed no vascular involvement, unlike all males (n=23) in the pedigrees (p=0.001).
- Males exhibited a higher risk of vascular complications (p=0.037), with a significant difference in aortic root/ascending aorta involvement compared to females (4% vs 32%, p=0.034).
- In the combined cohort (220 patients), males were over-represented (p<0.001), and non-penetrance for aortic root/ascending aorta pathology was higher in females (p=0.028).
Conclusions:
- Non-penetrance of vascular pathology is more prevalent in women carrying SMAD3 variants.
- Normal echocardiography in at-risk females may not fully exclude the risk of vasculopathy in other arterial locations.
- Higher non-penetrance in women contributes to ascertainment bias, leading to an over-representation of males in published SMAD3 literature.
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.
Related Concept Videos
01:33Pleiotropy
02:50Dosage Compensation
In addition to sexual development, the X chromosome has genes involved in autosomal functions such as brain development and the immune system. Therefore, males and females with distinct numbers of X chromosomes will...
02:19The Y Chromosome Determines Maleness
Evolution
Around 300 million years ago, the two sex chromosomes diverged from two identical autosomal chromosomes. Over time, the Y chromosome has lost most of its genes, shrinking in size....
02:45The Ratio of X Chromosome to Autosomes
Normal male Drosophila has a ratio of one X chromosome to two sets of autosomes. In contrast, normal female...
01:19X-linked Traits
01:35Pedigree Analysis