Rare syndromic craniosynostosis or isolated multisuture synostosis

Gene: SOX6

Green List (high evidence)

Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there is sufficient evidence available (seven unrelated cases) for this gene to be promoted to GREEN rating in the next GMS update.

In addition, this gene has also been associated with relevant phenotypes in both OMIM (MIM #618971 ) and Gene2Phenotype (with 'strong' rating in the DD panel).

Created: 11 May 2023, 10:58 a.m. | Last Modified: 11 May 2023, 10:58 a.m.

Panel Version: 4.48

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Tolchin-Le Caignec syndrome, OMIM:618971

Publications

• 16258006
• 32442410
• 36118902
• 36980886

Green List (high evidence)

A resequencing analysis of 617 individuals without a genetic basis to their craniosynostosis identified two individuals with loss of function variants in SOX6: c.436_445+13del; p.(?), and c.1624G>T; p.(Glu542*): doi.org/10.3390/genes14030615 (Tooze et al., 2023).

There are three unrelated patients with loss-of-function variants in SOX6 reported in the Tolchin et al., 2020 paper.

A further individual was found with a stop-gain variant in SOX6 in a whole exome sequencing analysis of 102 panel-undiagnosed patients in China (c.1243C>T; p.(Gln415*)) (Chen et al., 2022).

One patient was described with a balanced translocation affecting SOX6 (as commented by EW previously).

In total, 7 independent families are described in the literature with loss of function variants in SOX6 and craniosynostosis.

Created: 2 Mar 2023, 12:07 p.m. | Last Modified: 2 Mar 2023, 12:07 p.m.

Panel Version: 3.4

I don't know

Tolchin et al, 2020 - SOX6 variants associated with SOXopathy. Idenitifed 19 individuals from 17 unrealted families harbouring various types of het SOX6 alterations exhibiting developmental delay and or intellectual disability, 14 de novo. 3 unrelated individuals also presented with a craniosynotosis phenotype: CHUP-1 - de nov del of exons 5-7 with metopic, sagittalcoronal synostosis; UK-1 de novo nonsense variant, S81* with sagittal synostosis and UK-2 nonsense variant, Arg93* with sagittal and left coronal synostosis - inheritance unknown. Not enough evidence to make this a green gene.

Created: 22 Jan 2021, 2 p.m. | Last Modified: 22 Jan 2021, 2 p.m.

Panel Version: 2.19

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Developmental delay; intellectual disability; craniosynostosis

Publications

• 32442410

Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).

Created: 20 Oct 2020, 2:17 p.m. | Last Modified: 20 Oct 2020, 2:17 p.m.

Panel Version: 2.10

Red List (low evidence)

Balanced translocation in a patient with CSS disrupts SOX6 (Tagariello et al 2005).Further case identified with missense change (inherited). ; Review on behalf of Tracy Lester and Andrew Wilkie

Created: 5 Mar 2019, 11:33 a.m.

Phenotypes
No disease association on OMIM

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, 11:55 a.m. | Last Modified: 11 Oct 2023, 11:55 a.m.

Panel Version: 4.174

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed. No new evidence. For-review tag should have been removed after Helen Lord review in Jan 2021.

Created: 5 Mar 2022, 5:41 p.m. | Last Modified: 5 Mar 2022, 5:41 p.m.

Panel Version: 2.63

3 unrelated cases reported in Tolchin et al, 2020 with a craniosynotosis phenotype but segregation data only for 2 patients.. Additional evidence in Tagariello et al 2004 who reports a patient with brachycephaly and a translocation disrupting SOX6. Borderline green/amber but based on review by Expert Reviewer Helen Lord, will keep amber for now.

Created: 26 Jan 2021, 4:56 p.m. | Last Modified: 26 Jan 2021, 5:02 p.m.

Panel Version: 2.22

Comment on mode of inheritance: All patients reported by Tolchin et al were heterozygous

Created: 25 May 2020, 2:27 p.m. | Last Modified: 25 May 2020, 2:27 p.m.

Panel Version: 2.6

Comment on list classification: 4 patients reported with genomic alterations affecting SOX6 are now reported.

Created: 25 May 2020, 2:27 p.m. | Last Modified: 25 May 2020, 2:27 p.m.

Panel Version: 2.5

PMID: 32442410 -Tolchin et al 2020 - report 3 unrelated patients (CHUP-1;406931, UK-1;412103 and UK-2;412119) with either deletion of exons 5–7 or nonsense variants (c.242C>G p.Ser81*, c.277C>T p.Arg93*). Patients had a range of phenotypes including mild to moderate intellectual disability, attention deficit/ADHD and either oxycephaly or scaphocephaly. The first two patients had de-novo variants, in the third this is unknown. 16 other patients from 14 families were also reported with variants in SOX6 but no craniosynostosis phenotype.

PMID: 16258006 - Tagariello et al 2004 - a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. The complete coding sequence of the FGFR2 and FGFR3 genes were screened but no variants found. The P252R mutation in the FGFR1 gene was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes.

Created: 25 May 2020, 2:24 p.m. | Last Modified: 26 Jan 2021, 4:47 p.m.

Panel Version: 2.22

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: SOX6; Suggested initial gene rating: red

Created: 5 Mar 2019, 11:21 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted