Thoracic aortic aneurysm and dissection

Gene: SMAD4

Green List (high evidence)

SMAD4 (SMAD family member 4)
EnsemblGeneIds (GRCh38): ENSG00000141646
EnsemblGeneIds (GRCh37): ENSG00000141646
OMIM: 600993, Gene2Phenotype
SMAD4 is in 26 panels

9 reviews

Kate Thomson (Oxford University Hospitals Foundation Trust)

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

Ivone Leong (Genomics England Curator)

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

James Eden (Manchester)

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: 2 Oct 2019, 11:27 a.m. | Last Modified: 2 Oct 2019, 11:27 a.m.
Panel Version: 0.30

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

Phenotypes
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 175050; Myhre syndrome 139210; Pancreatic cancer, somatic 260350; Polyposis, juvenile intestinal 174900

Publications

Matthew Edwards (Clinical Genetics & Genomics Lab, Royal Brompton & Harefield NHS Trust)

I don't know

Some evidence, but ? enough
Created: 18 Sep 2019, 8:55 p.m. | Last Modified: 18 Sep 2019, 8:55 p.m.
Panel Version: 0.30

Publications

Alison Callaway (Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust)

I don't know

Missense variants at codon 500 (and 496) are associated with Myhre syndrome (OMIM #139210), which overlaps with a cardiac phenotype. The variants were reported to be de novo in this paper, suggesting a hotspot. Michot et al. Eur. J. Hum. Genet. 2014 ;22:1272-1277.

Loss-of-function in SMAD4 is associated with juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia. Aortopathy may be part of the phenotypic spectrum. Heald et al. Am J Med Genet A. 2015;167A:1758-62
Created: 29 Aug 2019, 2:04 p.m. | Last Modified: 29 Aug 2019, 2:04 p.m.
Panel Version: 0.5

Phenotypes
Myhre syndrome

Publications

Rebecca Whittington (South West GLH)

I don't know

139210 Myhre syndrome - syndromic with cardiac abnormalities including aortic stenosis/coarctation. HGMD - 6 variants for Myher syndrome but phenotype varies for patients with same variant.
Created: 25 Mar 2019, 4:30 p.m.
Wain et al 2014 Genet Med 16:588 reviews clinical features of patients with SMAD4 variants and identifies enlarged aortic root in 9% (3 patients) and aortic dissection in one patient. References other publications that refer to a Marfan-like presentation.
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

Nick Camm (NHS)

Green List (high evidence)

Ellen McDonagh (Genomics England Curator)

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.
Not on the Inherited Cardiac Condition Genes panel for Familial aortic anuerysm reported in: Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes, Pua et al, Journal of Cardiovascular Translational Research, online Feb 2016 (doi:10.​1007/​s12265-016-9673-5). The panel contains disease-causing, putatively pathogenic, research and phenocopy genes.
Created: 19 Feb 2016, 10:58 a.m.

Matina Prapa (Genomics England Curator)

Green List (high evidence)

SMAD 4 part of the TGFβ pathway with integral role of the latter in TAAD, including Marfan and Loeys-Dietz syndrome. In retrospective study of HHT patients, aortopathy was found in 6/26 (23%) patients out of which all had SMAD4 mutations (PMID: 25931195).
Created: 14 Feb 2016, 3:08 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
175050- Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Publications

History Filter Activity

9 Dec 2019, Gel status: 3

Added New Source, Status Update

Ivone Leong (Genomics England Curator)

Source Expert Review Green was added to SMAD4. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

18 Apr 2019, Gel status: 2

Created, Added New Source, Set mode of inheritance, Set Phenotypes

Ellen McDonagh (Genomics England Curator)

gene: SMAD4 was added gene: SMAD4 was added to GMS FTAAD placeholder panel. Sources: Expert Review Amber,London South GLH,South West GLH Mode of inheritance for gene: SMAD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: SMAD4 were set to Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, 175050