Craniosynostosis

Gene: SMAD6

Green List (high evidence)

SMAD6 (SMAD family member 6)
EnsemblGeneIds (GRCh38): ENSG00000137834
EnsemblGeneIds (GRCh37): ENSG00000137834
OMIM: 602931, Gene2Phenotype
SMAD6 is in 7 panels

4 reviews

Tracy Lester (Genetics laboratory, Oxford UK)

Green List (high evidence)

Low penetrance variants associated with non-syndromic sagittal synostosis. Amber (AD). Weakly penetrant variants associated with non-syndromic CSS (TL). Strongly support green: Timberlake eLife 16 and PNAS 17 papers presented strong evidence for enrichment of LOF mutations and supported by own work (20-fold over background in population). Implications for interpetation of wider syndromic phenotypes (AW). Note added by GOSH - 76% clinical exome coverage ; Review on behalf of Tracy Lester/Andrew Wilkie
Created: 5 Mar 2019, 11:33 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
metopic synostosis; sagittal synostosis; {Craniosynostosis 7, susceptibility to} 617439

Publications

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

Eleanor Williams (Genomics England Curator)

I don't know

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: SMAD6; Suggested initial gene rating: green
Created: 5 Mar 2019, 11:21 a.m.

Andrew Wilkie (University of Oxford)

Green List (high evidence)

Own unpublished data confirm significant enrichment in metopic synostosis (~6%) and sagittal synostosis (~2%), associated with incomplete penetrance. Associated BMP2 SNP genotyping not clinically useful. Gene is being added as diagnostic in Oxford lab. Clear loss-of-function mutations could be considered pathogenic, albeit with reduced penetrance. Greater caution required for missense mutations (ideally requires functional assay). Note that a similar spectrum of mutations reported in bicuspid aortic valve and ascending thoracic aortic aneurysm, with important implications for genetic counselling and cardiac screening.
Created: 18 Oct 2017, 8:55 a.m.
Proposed digenic inheritance of a loss of function allele at SMAD6 and the high risk (C) allele at (presumed BMP2-regulatory) SNP rs1884302. Data look convincing but require independent replication given the unusual genetic mechanism.
Created: 11 Nov 2016, 12:35 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
metopic synostosis; sagittal synostosis; bicuspid aortic valve; thoracic aortic aneurysm

Publications

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

Ellen McDonagh (Genomics England Curator)

Comment on list classification: Promoted to green after feedback from Richard Scott (Genomics England Clinical Lead for Rare Disease), as the degree of non-penetrance is within the limits of what would be report on diagnostically.
Created: 14 Dec 2017, 4:04 p.m.
Comment on list classification: Reported in 17 probands, however incomplete penetrance as 10 parents carried the variant, and relationship with risk allele of rs1884302 downstream BMP2.
Created: 15 Aug 2017, 12:08 p.m.

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • NHS GMS
  • Expert Review Green
Phenotypes
  • metopic synostosis
  • sagittal synostosis
  • {Craniosynostosis 7, susceptibility to} 617439
Tags
curated-variant-list polygenic
OMIM
602931
Clinvar variants
Variants in SMAD6
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

5 Mar 2019, Gel status: 3

Added New Source, Status Update

Eleanor Williams (Genomics England Curator)

Source NHS GMS was added to SMAD6. Rating Changed from Green List (high evidence) to Green List (high evidence)

14 Dec 2017, Gel status: 3

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for SMAD6 were set to 27606499; 23438589; 28808027; 28659821

14 Dec 2017, Gel status: 3

Set mode of inheritance

Ellen McDonagh (Genomics England Curator)

Mode of inheritance for SMAD6 was changed from Other - please specifiy in evaluation comments to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

14 Dec 2017, Gel status: 3

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

15 Aug 2017, Gel status: 1

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

15 Aug 2017, Gel status: 1

Set Phenotypes

Ellen McDonagh (Genomics England Curator)

Phenotypes for SMAD6 were set to metopic synostosis; sagittal synostosis; {Craniosynostosis 7, susceptibility to} 617439

15 Aug 2017, Gel status: 1

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for SMAD6 were set to 27606499;23438589

15 Aug 2017, Gel status: 1

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

11 Nov 2016, Gel status: 0

Created

Andrew Wilkie (University of Oxford)

SMAD6 was created by awilkie

11 Nov 2016, Gel status: 0

Added New Source

Andrew Wilkie (University of Oxford)

SMAD6 was added to Craniosynostosis syndromes phenotypespanel. Sources: Literature