TY - JOUR
T1 - Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: Further delineation of the phenotype
AU - Cannaerts, Elyssa
AU - Kempers, Marlies
AU - Maugeri, Alessandra
AU - Marcelis, Carlo
AU - Gardeitchik, Thatjana
AU - Richer, Julie
AU - Micha, Dimitra
AU - Beauchesne, Luc
AU - Timmermans, Janneke
AU - Vermeersch, Paul
AU - Meyten, Nathalie
AU - Chénier, S. bastien
AU - van de Beek, Gerarda
AU - Peeters, Nils
AU - Alaerts, Maaike
AU - Schepers, Dorien
AU - van Laer, Lut
AU - Verstraeten, Aline
AU - Loeys, Bart
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
KW - SMAD2
KW - aortic aneurysm and dissection
KW - arterial aneurysmal disease
KW - connective tissue disease
KW - loeys-dietz syndrome
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85063325812&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29967133
U2 - https://doi.org/10.1136/jmedgenet-2018-105304
DO - https://doi.org/10.1136/jmedgenet-2018-105304
M3 - Article
C2 - 29967133
SN - 0022-2593
VL - 56
SP - 220
EP - 227
JO - Journal of medical genetics
JF - Journal of medical genetics
IS - 4
ER -