Rare syndromic craniosynostosis or isolated multisuture synostosis
Gene: SMAD6
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 WilkieCreated: 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
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: greenCreated: 5 Mar 2019, 11:21 a.m.
Own unpublished data confirm significant enrichment in metopic synostosis (~6%) and sagittal synostosis (~2%), associated with incomplete penetrance.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
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.
Source NHS GMS was added to SMAD6. Rating Changed from Green List (high evidence) to Green List (high evidence)
Publications for SMAD6 were set to 27606499; 23438589; 28808027; 28659821
Mode of inheritance for SMAD6 was changed from Other - please specifiy in evaluation comments to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
This gene has been classified as Green List (High Evidence).
This gene has been classified as Red List (Low Evidence).
Phenotypes for SMAD6 were set to metopic synostosis; sagittal synostosis; {Craniosynostosis 7, susceptibility to} 617439
Publications for SMAD6 were set to 27606499;23438589
This gene has been classified as Red List (Low Evidence).
SMAD6 was created by awilkie
SMAD6 was added to Craniosynostosis syndromes phenotypespanel. Sources: Literature