Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: Further delineation of the phenotype

Elyssa Cannaerts, Marlies Kempers, Alessandra Maugeri, Carlo Marcelis, Thatjana Gardeitchik, Julie Richer, Dimitra Micha, Luc Beauchesne, Janneke Timmermans, Paul Vermeersch, Nathalie Meyten, S. bastien Chénier, Gerarda van de Beek, Nils Peeters, Maaike Alaerts, Dorien Schepers, Lut van Laer, Aline Verstraeten, Bart Loeys

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)220-227
JournalJournal of Medical Genetics
Volume56
Issue number4
DOIs
Publication statusPublished - 2019

Cite this

Cannaerts, Elyssa ; Kempers, Marlies ; Maugeri, Alessandra ; Marcelis, Carlo ; Gardeitchik, Thatjana ; Richer, Julie ; Micha, Dimitra ; Beauchesne, Luc ; Timmermans, Janneke ; Vermeersch, Paul ; Meyten, Nathalie ; Chénier, S. bastien ; van de Beek, Gerarda ; Peeters, Nils ; Alaerts, Maaike ; Schepers, Dorien ; van Laer, Lut ; Verstraeten, Aline ; Loeys, Bart. / Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: Further delineation of the phenotype. In: Journal of Medical Genetics. 2019 ; Vol. 56, No. 4. pp. 220-227.
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title = "Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: Further delineation of the phenotype",
abstract = "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.",
author = "Elyssa Cannaerts and Marlies Kempers and Alessandra Maugeri and Carlo Marcelis and Thatjana Gardeitchik and Julie Richer and Dimitra Micha and Luc Beauchesne and Janneke Timmermans and Paul Vermeersch and Nathalie Meyten and Ch{\'e}nier, {S. bastien} and {van de Beek}, Gerarda and Nils Peeters and Maaike Alaerts and Dorien Schepers and {van Laer}, Lut and Aline Verstraeten and Bart Loeys",
year = "2019",
doi = "10.1136/jmedgenet-2018-105304",
language = "English",
volume = "56",
pages = "220--227",
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Cannaerts, E, Kempers, M, Maugeri, A, Marcelis, C, Gardeitchik, T, Richer, J, Micha, D, Beauchesne, L, Timmermans, J, Vermeersch, P, Meyten, N, Chénier, SB, van de Beek, G, Peeters, N, Alaerts, M, Schepers, D, van Laer, L, Verstraeten, A & Loeys, B 2019, 'Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: Further delineation of the phenotype' Journal of Medical Genetics, vol. 56, no. 4, pp. 220-227. https://doi.org/10.1136/jmedgenet-2018-105304

Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: Further delineation of the phenotype. / Cannaerts, Elyssa; Kempers, Marlies; Maugeri, Alessandra; Marcelis, Carlo; Gardeitchik, Thatjana; Richer, Julie; Micha, Dimitra; Beauchesne, Luc; Timmermans, Janneke; Vermeersch, Paul; Meyten, Nathalie; Chénier, S. bastien; van de Beek, Gerarda; Peeters, Nils; Alaerts, Maaike; Schepers, Dorien; van Laer, Lut; Verstraeten, Aline; Loeys, Bart.

In: Journal of Medical Genetics, Vol. 56, No. 4, 2019, p. 220-227.

Research output: Contribution to journalArticleAcademicpeer-review

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

Y1 - 2019

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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/29967133

U2 - 10.1136/jmedgenet-2018-105304

DO - 10.1136/jmedgenet-2018-105304

M3 - Article

VL - 56

SP - 220

EP - 227

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 4

ER -