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SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium
  1. Ellen M Hostetler1,
  2. Ellen S Regalado1,
  3. Dong-Chuan Guo1,
  4. Nadine Hanna2,3,
  5. Pauline Arnaud2,3,
  6. Laura Muiño-Mosquera4,
  7. Bert Louis Callewaert4,
  8. Kwanghyuk Lee5,
  9. Suzanne M Leal5,
  10. Stephanie E Wallace1,
  11. Andrea L Rideout6,
  12. Sarah Dyack6,7,
  13. Rajani D Aatre8,
  14. Catherine Boileau2,9,
  15. Julie De Backer4,
  16. Guillaume Jondeau9,10,
  17. Dianna M Milewicz1
  1. 1 Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, Texas, USA
  2. 2 Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France
  3. 3 Laboratory for Vascular Translational Science, INSERM U1148, Université Paris Diderot, Hôpital Bichat, Paris, France
  4. 4 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
  5. 5 Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  6. 6 Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada
  7. 7 Department of Pediatrics and Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
  8. 8 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
  9. 9 Centre de référence pour le syndrome de Marfan et apparentés, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Faculté Paris Diderot, LVTS INSERM U 1148, Paris, France
  10. 10 Service de Cardiologie, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France
  1. Correspondence to Dianna M Milewicz, University of Texas Health Science Center, Houston, TX 77030, USA; Dianna.M.Milewicz{at}


Background Pathogenic variants in SMAD3 cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Here, we examined differences in clinical presentation of aortic events (dissection or surgical repair of an aneurysm) with respect to age and variant type in an international cohort of individuals with SMAD3 variants.

Methods Aortic status and events, vital status and clinical features were abstracted through retrospective review of medical records of 212 individuals with 51 unique SMAD3 variants, including haploinsufficiency (HI) and missense substitutions in the MH2 domain, as well as novel in-frame deletions and missense variants in the MH1 domain.

Results Aortic events were documented in 37% of cases, with dissections accounting for 70% of events. The median age at first aortic event was significantly lower in individuals with SMAD3 MH2 missense variants than those with HI variants (42years vs 49 years; p=0.003), but there was no difference in frequency of aortic events by variant type. The cumulative risk of an aortic event was 50% at 54 years of age. No aortic events in childhood were observed.

Conclusions SMAD3 pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. Of the covariates examined, the type of underlying SMAD3 variant was responsible for some of this variation. Later onset of aortic events and the absence of aortic events in children associated with SMAD3 variants support gene-specific management of this disorder.

  • connective tissue disease
  • genetics
  • cardiovascular medicine
  • clinical genetics

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  • Contributors EMH, ESR and DMM planned the study and wrote the manuscript. DG, KL and SML performed bioinformatics and statistical analyses. DG performed the computational analyses on the effect of missense variants. EMH wrote the draft of the manuscript. EMH, ESR, CB, JDB, GJ and DMM contributed to the results, discussion and added revisions at all stages. GJ, NH and PA abstracted, analysed and summarized the clinical data for patients recruited in France. LM-M and BLC abstracted, analysed and summarised the clinical data for patients recruited in Belgium. EMH, ESR and SEW abstracted, analysed and summarised the clinical data for patients recruited in Houston. ALR, SD and RDA phenotyped, collected clinical data and recruited patients from their practices. BLC and JDB are senior clinical investigators of the Research Foundation - Flanders.

  • Funding The following provided funding for this study: National Institutes of Health (RO1 HL62594 and P01HL110869-01), the John Ritter Research Foundation, Genetic Aortic Disorders Association of Canada, the Temerty Family Fund, French Ministry of Health (PHRC AOM09093;AOM10108); French Agency for Research (ANR-14-CE15-0012).

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval Committee For the Protection of Human Subjects - University of Texas Health Science Center at Houston Institutional Review Board.

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