Thoracic aortic aneurysm or dissection
Gene: SMAD4
Missense variants at codon 500 (and 496) are associated with Myhre syndrome, 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:1758-62Created: 8 May 2019, 2:07 p.m.
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
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
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.
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
Source South West GLH was added to SMAD4.
Source London South GLH was added to SMAD4. Rating Changed from Green List (high evidence) to Green List (high evidence)
Phenotypes for SMAD4 were set to Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, 175050
Phenotypes for SMAD4 were set to Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, 175050
Publications for SMAD4 were set to 26699655; 23239472; 25931195
This gene has been classified as Green List (High Evidence).
Mode of inheritance for SMAD4 was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
This gene has been classified as Green List (High Evidence).
SMAD4 was added to Familial thoracic aortic aneurysms and dissectionpanel. Sources: Expert list