Background Missense variants in SMAD2, encoding a key transcriptional regulator of transforming growth factor beta signalling, were recently reported to cause arterial aneurysmal disease.
Objectives The aims of the study were to identify the genetic disease cause in families with aortic/arterial aneurysmal disease and to further define SMAD2 genotype–phenotype correlations.
Methods and results Using gene panel sequencing, we identified a SMAD2 nonsense variant and four SMAD2 missense variants, all affecting highly conserved amino acids in the MH2 domain. The premature stop codon (c.612dup; p.(Asn205*)) was identified in a marfanoid patient with aortic root dilatation and in his affected father. A p.(Asn318Lys) missense variant was found in a Marfan syndrome (MFS)-like case who presented with aortic root aneurysm and in her affected daughter with marfanoid features and mild aortic dilatation. In a man clinically diagnosed with Loeys-Dietz syndrome (LDS) that presents with aortic root dilatation and marked tortuosity of the neck vessels, another missense variant, p.(Ser397Tyr), was identified. This variant was also found in his affected daughter with hypertelorism and arterial tortuosity, as well as his affected mother. The third missense variant, p.(Asn361Thr), was discovered in a man presenting with coronary artery dissection. Variant genotyping in three unaffected family members confirmed its absence. The last missense variant, p.(Ser467Leu), was identified in a man with significant cardiovascular and connective tissue involvement.
Conclusion Taken together, our data suggest that heterozygous loss-of-function SMAD2 variants can cause a wide spectrum of autosomal dominant aortic and arterial aneurysmal disease, combined with connective tissue findings reminiscent of MFS and LDS.
- aortic aneurysm and dissection
- arterial aneurysmal disease
- connective tissue disease
- loeys-dietz syndrome
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AV and BL shared last authors
Contributors EC carried out sequencing and analysis of DNA samples and drafted the manuscript. MK, AM, CM, TG, JR, DM, LB, JT, NM, PV, SC and BL collected DNA samples and contributed to accumulation and interpretation of clinical data. NP and GvdB carried out sequencing and analysis of DNA samples. DS, LVL, AV, MA and BL contributed to writing the manuscript. All authors read and approved the final manuscript.
Funding This research was supported by funding from the University of Antwerp (Lanceringsproject), the Fund for Scientific Research, Flanders (FWO, Belgium) (G.0221.12; G.0356.17), the Dutch Heart Foundation (2013T093 BAV) and the Foundation Leducq (MIBAVA – Leducq 12CVD03). BL is a senior clinical investigator of the Fund for Scientific Research, Flanders (FWO, Belgium) and holds a starting grant from the European Research Council (ERC- StG-2012-30972-BRAVE). AV is supported by a postdoctoral fellowship of the Fund for Scientific Research, Flanders (FWO, Belgium).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Approval for this study was obtained from the Ethics Committee of the Antwerp University Hospital/University of Antwerp.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The data sets used and analysed during the current study are available from the corresponding author on reasonable request.
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