Thoracic aortic aneurysm or dissection

Gene: SMAD2

As a result of watchlist tag audit the watchlist tag was removed from SMAD2- this is now a green gene with sufficient evidence/review

Created: 13 Jan 2020, 4:51 p.m. | Last Modified: 13 Jan 2020, 4:51 p.m.

Panel Version: 1.112

Green List (high evidence)

No OMIM association; HGMD Loeys-Dietz syndrome

Created: 25 Mar 2019, 4:30 p.m.

Schepers et al 2018 Hum Mutat 39:621 PMID:29392890 review variants in TGFB2/3 and SMAD2/3 in LDS, listing 6 likely pathogenic variants from this and previous studies. All missense variants to date

Created: 25 Mar 2019, 4:27 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Variants in this GENE are reported as part of current diagnostic practice

I don't know

This gene was part of an initial gene list collated by Matthew Edwards Royal Brompton Hospital sent 16th Jan 2019 on behalf of the London South GLH for review by the GMS Cardiology Specialist Group. Only gene symbol from the Royal Brompton gene panel was provided - suggested initial gene rating and evidence for inclusion not provided with the list.

Created: 20 Feb 2019, 2:17 p.m.

Green List (high evidence)

Comment when marking as ready: Meets evidence criteria in terms of three unrelated families reported. Only a single paper to date therefore tagged as watchlist in case further evidence emerges to the contrary. To be reviewed in the light of any new evidence.

Created: 26 Jul 2017, 8:44 a.m.

Comment on mode of pathogenicity: Missense variation reported to date. Some evidence to suggest upregulation of SMAD2. Further cases required to confirm scope of causative variation

Created: 26 Jul 2017, 8:43 a.m.

Comment on list classification: Meets evidence criteria - three unrelated families reported

Created: 26 Jul 2017, 8:41 a.m.

PMID 26247889 contains information about three unrelated cases with vascular disease, identified to have sequence variants in SMAD2. These are all missense variants, consdered to be pathogenic, with evidence of involvement in TGFbeta signalling and increased expression of SMAD2. I cannot find any contradictory evidence. The clinical phenotypes are an appropriate fit for this panel, however the evidence to date suggests that this is likely to be a relatively rare cause (3 from a cohort of 365).

Created: 26 Jul 2017, 8:36 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Arterial aneurysms and dissections

Publications

• 26247899

Mode of pathogenicity
Other

PMID:26247899 (2015) report 3 families with arterial aneurysms and dissections with pathogenic variants in SMAD2:
Patient P1-1: c.1346T>C, p.(Leu449Ser). Patient P2-1: c.1369G>A, p.(Gly457Arg) de novo variant. Patients P3-1 and P3-2 (affected siblings): c.1163A>G, p.(Gln388Arg).

Created: 25 Jul 2017, 3 p.m.

Added SMAD2 to panel as advised by reviewer of the Ehlers-Danlos syndrome (EDS) panel, Neeti Ghali, and Fleur Van Dijk (author of PMID:26247899).

Created: 25 Jul 2017, 3 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
arterial aneurysms and dissections

Publications

• 26247899