Aortopathy_Connective Tissue Disorders

Gene: SMAD6

Comment when marking as ready: Primarily associated with aortic valve disease, but increased prevalence of thoracic aneurysm also documented.

Created: 1 Jul 2020, 6:22 a.m. | Last Modified: 1 Jul 2020, 6:22 a.m.

Panel Version: 0.115

I don't know

Missense and LOF SMAD6 variants described as pathogenic or likely pathogenic have been identified in at least 20 individuals from bicuspid aortic valve/nonsyndromic thoracic aortic aneurysm cohorts (PMID:22275001, 30848080, 28659821, 30796334).

Functional studies on two of the missense variants supported abnormal function, but a third variant did not show any functional defect (and was also not well-conserved) (PMID:22275001).

Familial segregation studies in PMID: 30796334 demonstrated reduced penetrance (82%) and variable clinical expressivity, with coarctation of the aorta being a common comorbidity.

Biallelic variants have been decribed in 2 individuals with 'complex cardiac phenotype' (including aortic isthmus stenosis, dysplastic and stenotic pulmonary valve, and dilated cardiomyopathy) (PMID: 30963242).

There appears to be a clear gene-disease relationship but I am not sure if it belongs in this panel.
Sources: Literature

Created: 1 Jul 2020, 2:49 a.m.

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

Phenotypes
Aortic valve disease 2 MIM# 614823

Publications

• 22275001
• 28659821
• 30963242
• 30848080
• 30796334

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