Aortopathy_Connective Tissue Disorders

Gene: SMAD4

Green List (high evidence)

"Limited evidence" for association with aortic dilatation/dissection by ClinGen:

"Eight genes scored as moderate (EFEMP2) or limited (ELN, FBN2, FLNA, NOTCH1,
SLC2A10, SMAD4, and SKI) for association with HTAAD. These genes are a heterogeneous group for which the evidence was often difficult to assess...the evidence, therefore, for their association with a presentation of aortic dilatation and/or dissection is often rather lacking. The other common feature of these conditions is that there is no robust evidence of progression to aortic dissection."


Green in PanelApp UK although with quite a few Amber reviews.

There is an association between people with with SMAD4 variants and aortic dissection (PMID 25931195). The ClinGen review of SMAD4, viewable in the supplementary material, dates to 22/12/2016 and so does not account for the reported individuals in PMID 30809044. Given this more recent data Green is appropriate.

Created: 25 Jun 2020, 2:51 a.m. | Last Modified: 25 Jun 2020, 6:30 a.m.

Panel Version: 0.30

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

Phenotypes
Hereditary thoracic aortic aneurysm and dissection

Publications

• 30071989
• 25931195
• 25931195
• 30809044

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

Green List (high evidence)

SMAD4 pathogenic variants cause juvenile polyposis (JPS) and hereditary hemorrhagic telangiectasia (HHT), and 40% of affected individuals also have thoracic aortic disease. Three individuals recently reported with rare/novel missense and isolated thoracic aortic aneurysm.
Sources: Literature

Created: 22 Apr 2020, 5:24 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, MIM# 175050; Thoracic aortic aneurysm

Publications

• 30809044