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Genotype-phenotype correlations
Original research
Sexual dimorphism in SMAD3 pathogenic variant-harbouring individuals
  1. Julie Richer1,2,
  2. Joe Davis Velchev3,
  3. Sharan Goobie4,
  4. Christie A Boswell-Patterson1,
  5. Ingrid M B H van de Laar5,
  6. Judith M A Verhagen5,
  7. Marja W Wessels5,
  8. Jolien W Roos-Hesselink6,
  9. Ilse Luyckx3,
  10. Hussein Al-Amodi7,
  11. Michael W A Chu7,
  12. Anne-Marie Laberge8,
  13. Bekim Sadikovic9,
  14. Tugce Balci10,
  15. Aline Verstraeten3,
  16. Bart Loeys3
  1. 1 Department of Medical Genetics, Children's Hospital of Eastern Ontario Regional Genetics Program, Ottawa, Ontario, Canada
  2. 2 Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
  3. 3 Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
  4. 4 Medical Genetics, Pediatrics, IWK Health Centre, Halifax, Ontario, Canada
  5. 5 Department of Clinical Genetics, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands
  6. 6 Department of Cardiology, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands
  7. 7 Division of Cardiac Surgery, Western University , London , Ontario , Canada
  8. 8 Medical Genetics, Department of Pediatrics, CHU Ste-Justine, Montreal, Quebec, Canada
  9. 9 Department of Pathology and Laboratory Medicine, London Health Sciences Centre , London, Ontario , Canada
  10. 10 Department of Pediatrics, Division of Medical Genetics, Western University, London, Ontario , Canada
  1. Correspondence to Dr Julie Richer; juricher{at}cheo.on.ca

Abstract

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.

  • Aneurysm
  • Phenotype
  • Disease Management
  • Heart Aneurysm
  • Pedigree

Data availability statement

Data are available on reasonable request. Deidentified data is available from ORCID 0000-0003-3703-9518. Reuse of such data is not permitted.

https://doi.org/10.1136/jmg-2024-110219

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    Data availability statement

    Data are available on reasonable request. Deidentified data is available from ORCID 0000-0003-3703-9518. Reuse of such data is not permitted.

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    Footnotes

    • X @MichaelMwachu

    • JR and JDV contributed equally.

    • Contributors JR and BL were responsible for the conception of this work. JR produced the first draft. JDV did the statistical work. JR, JDV and BL work iteratively on this manuscript. Nearly all coauthors contributed to collection of clinical data. All coauthors contributed to critical appraisal/manuscript revision. BL is the guarantor.

    • Funding This research was largely supported by funding from the University of Antwerp (GOA 33933; Methusalem-OEC grant ‘Genomed’ 40709), the Research Foundation Flanders (FWO, Belgium, G044720N), the Dutch Heart Foundation (2013T093) and the Belgian Cardiac Surgery Foundation and the Marfan Foundation. BL holds a consolidator grant from the European Research Council (Genomia—ERC-COG-2017-771945). BL and AV are members of the European Reference Network on rare multisystemic vascular disorders (VASCERN—project ID: 769036 partly cofunded by the European Union Third Health Programme).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.