Thoracic aortic aneurysm or dissection (GMS)

Gene: SMAD2

Green List (high evidence)

Submitted on behalf of the GMS Cardiology specialist group. This gene did not achieve a consensus Green rating; however, the group agreed that the existing evidence (published and in-house data) was sufficient to support inclusion in this panel.

Created: 9 Dec 2019, 1:19 p.m. | Last Modified: 9 Dec 2019, 1:19 p.m.

Panel Version: 0.55

I don't know

Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Amber on this panel.

Created: 18 Nov 2019, 4:33 p.m. | Last Modified: 18 Nov 2019, 4:33 p.m.

Panel Version: 0.35

I don't know

See recent review from Bart Loeys team (Schepers et al 2009 PMID 29392890), also included in their TAAD panel. Limited information in the literature, amber gene list seems appropriate.

Created: 25 Sep 2019, 9:45 a.m. | Last Modified: 25 Sep 2019, 9:45 a.m.

Panel Version: 0.30

Publications

• 29392890

Green List (high evidence)

On CGGL Royal Brompton panel currently. Some good evidence in PMID: 26247899. PMID 29392890 describes variants classified in paper as likely pathogenic causing Loeys-Dietz syndrome, with aortic and aortic root aneurysm and arterial dissection and tortuosity

Created: 18 Sep 2019, 8:54 p.m. | Last Modified: 18 Sep 2019, 9:02 p.m.

Panel Version: 0.30

Phenotypes
Loeys-Dietz syndrome (not in OMIM)

Publications

• 26247899
• 29392890

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

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