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Mendeliome

Gene: SMAD6

Green List (high evidence)

SMAD6 (SMAD family member 6)
EnsemblGeneIds (GRCh38): ENSG00000137834
EnsemblGeneIds (GRCh37): ENSG00000137834
OMIM: 602931, Gene2Phenotype
SMAD6 is in 8 panels

1 review

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Green List (high evidence)

Radioulnar synostosis: Yang et al. (2019) performed exome sequencing on 117 patients with sporadic RUS and found significant enrichment for loss-of-function variants in the SMAD6 gene. Identified 22 SMAD6 rare variants (with a minor allele frequency of less than 0.0001) that occurred in 22 nonsyndromic RUS patients. Logistic regression showed that SMAD6 loss-of-function variants were significantly associated with increased risk of nonsyndromic RUS (OR 430; 95% CI 237.5-780.1; p less than 0.000001). Some inherited from unaffected parents.

Craniosynostosis: Penetrance is 57%. A common polymorphism near BMP2 (rs1884302) was initially proposed to influence penetrance, but follow-up study did not corroborate this. In vitro luciferase assays suggest loss of SMAD6 inhibitory function.

Aortic valve disease: 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).
Created: 6 Jan 2022, 5:15 a.m. | Last Modified: 6 Jan 2022, 5:15 a.m.
Panel Version: 0.10539

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
{Radioulnar synostosis, nonsyndromic} 179300; {Craniosynostosis 7, susceptibility to} 617439; Aortic valve disease 2 MIM# 614823

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Victorian Clinical Genetics Services
Phenotypes
  • {Radioulnar synostosis, nonsyndromic} 179300
  • {Craniosynostosis 7, susceptibility to} 617439
  • Aortic valve disease 2 MIM# 614823
OMIM
602931
Clinvar variants
Variants in SMAD6
Penetrance
None
Publications
Panels with this gene

History Filter Activity

6 Jan 2022, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: smad6 has been classified as Green List (High Evidence).

6 Jan 2022, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: SMAD6 were changed from to {Radioulnar synostosis, nonsyndromic} 179300; {Craniosynostosis 7, susceptibility to} 617439; Aortic valve disease 2 MIM# 614823

6 Jan 2022, Gel status: 3

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: SMAD6 were set to

6 Jan 2022, Gel status: 3

Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of inheritance for gene: SMAD6 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

17 Nov 2019, Gel status: 3

Created, Added New Source, Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

gene: SMAD6 was added gene: SMAD6 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: SMAD6 was set to Unknown