Rare syndromic craniosynostosis or isolated multisuture synostosis
Gene: SIX1
Unpublished work by AW identified 7 cases from 6 families with CSS - LOF instead of missense in BOR. Relatively common cause of mutations compared to many green genes. Known craniofacial disease gene (BOR syndrome) (AW) ; Review on behalf of Tracy Lester and Andrew WilkieCreated: 5 Mar 2019, 11:33 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
sagittal synostosis, multi-suture synostosis
The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 5 Mar 2022, 5:41 p.m. | Last Modified: 5 Mar 2022, 5:41 p.m.
Panel Version: 2.63
Comment on list classification: Leaving the rating at amber for now, but with recommendation for green rating following the next GMS review. More than 3 cases with a craniosynostosis phenotype and variants in this gene now published.Created: 21 Jan 2021, 4:54 p.m. | Last Modified: 21 Jan 2021, 4:54 p.m.
Panel Version: 2.17
Comment on list classification: Upgrading from red to amber. Amber rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13. The group decided to rate Amber due to several unpublished cases.Created: 21 May 2019, 4:12 p.m.
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: SIX1; Suggested initial gene rating: amberCreated: 5 Mar 2019, 11:21 a.m.
Calpena et al (2021) identified 7 families in which the proband had craniosynostosis (affecting at least the sagittal suture in all cases) and a heterozygous SIX1 variant (4 nonsense + 3 missense in highly conserved residues of SIX domain or homeodomain). SIX1 mutations (mostly missense) were previously described in branchio-otic syndrome (BOS). Patients and carriers in the extended family variably had features of BOS (including branchial cysts, ear tags or pits, and hearing loss), but there were also several non-penetrant heterozygous individuals, indicating substantial variation in expressivity.
The absolute proportion of all craniosynostosis cases found to have SIX1 variants was low (7/1629, 0.4%), but much higher [4/23 (17%)] in those with the rare "Mercedez-Benz" pattern (sagittal + bilambdoid synostosis).
SIX1 analysis is therefore particularly indicated in individuals with either (1) additional BOS features or (2) sagittal+bilambdoid synostosis.Created: 19 Jan 2021, 11:08 a.m. | Last Modified: 19 Jan 2021, 11:08 a.m.
Panel Version: 2.16
Our unpublished work has identified 5 unrelated individuals heterozygous for rare missense (n=2) or nonsense (n=3) mutations in craniosynostosis (2 de novo and 3 inherited). This represents a clear enrichment. Note that there is a distinct genotype-phenotype correlation compared with BOR syndrome, which is usually caused by missense mutations in the SIX domain. By contrast, heterozygous lof seems to be associated with a milder phenotype associated with craniosynososis in some individuals +/- mild BOR features.Created: 18 Oct 2017, 9:02 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
sagittal synostosis, multi-suture synostosis
Publications
Publications for gene: SIX1 were set to
Tag for-review was removed from gene: SIX1.
Source Expert Review Green was added to SIX1. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Gene: six1 has been classified as Amber List (Moderate Evidence).
Tag for-review tag was added to gene: SIX1.
Gene: six1 has been classified as Amber List (Moderate Evidence).
Source NHS GMS was added to SIX1.
This proposed gene was validated and added to this panel
SIX1 was added to Craniosynostosis syndromes phenotypespanel. Sources: Expert Review
SIX1 was created by awilkie