Rare syndromic craniosynostosis or isolated multisuture synostosis

Gene: GNAS

Green List (high evidence)

PMID: 41307550 Yan et al., Nov 2025 - online ahead of print
Reported germline heterozygous variants in GNAS: three de novo missense variants (c.286A>G;p.K96E, c.758A>G;p.Y253C, and c.691C>T;p.R231C) and one maternally inherited splicing variant (c.1039-2A>G). Seq method: WES. Affected individuals presented with multiple-suture synostosis, dysmorphic features, brachydactyly, short stature, with or without hormone resistance.
Also created a zebrafish model, where heterozygous gnas inactivation recapitulated human phenotypes, including multiple-suture synostosis, craniofacial abnormalities, and short stature.

Created: 2 Jan 2026, 11:18 a.m. | Last Modified: 2 Jan 2026, 11:18 a.m.

Panel Version: 6.2

Publications

• 41307550

Green List (high evidence)

Graul-Neumann report a boy with MSS and PHP1A: not clear if CSS due to GNAS or 2nd disorder. Other cases reported but not known if investigated molecularly (Fitch 1982). May be rare complication. Further molecularly proven case in Adetayo J Craniofac Surg 17, plus further 5 unpublished cases with clear pathogenic mutations in Oxford (AW, pers.comm.) ; Review on behalf of Tracy Lester/Andrew Wilkie

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

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)

Phenotypes
pseudohypoparathyroidism type 1a 103580

Publications

• 19530187
• 26340332

I don't know

Comment on list classification: Upgrading from red to green. Green rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13. Andrew Wilkie of Wessex and West Midlands GLH confirmed unpublished cases.

Created: 21 May 2019, 12:29 p.m.

Comment on publications: Graul-Neumann et al 2009 - PMID: 19530187
Twigg et al 2015 - PMID: 26340332
Adetayo et al 2015 - PMID: 26267576

Created: 21 May 2019, 12:27 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: GNAS; Suggested initial gene rating: green

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

Red List (low evidence)

Craniosynostosis is rare complication of pseudohypoparathyroidism. Other clinical and biochemical features should be present to make this diagnosis

Created: 15 Sep 2015, 8:44 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)

Phenotypes
pseudohypoparathyroidism type 1a

Publications

• 19530187
• 26340332