Skeletal dysplasia

Gene: GNAS

Green List (high evidence)

Acromelic dysplasias gp of SD, disorganized development of skeletal components gp of SD. Several cases. Also mutated in ACTH-independent macronodular adrenal hyperplasia 219080 IC;Pseudohypoparathyroidism Ic 612462;Pseudopseudohypoparathyroidism 612463; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)

Phenotypes
McCune-Albright syndrome, somatic, mosaic 174800; Osseous heteroplasia, progressive 166350; Pseudohypoparathyroidism Ia 103580; Pseudohypoparathyroidism Ib 603233

I don't know

The mode of inheritance of this gene has been updated to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, 11:08 a.m. | Last Modified: 11 Oct 2023, 11:08 a.m.

Panel Version: 4.20

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; Initial rating suggestion: green

Created: 6 Mar 2019, 11:36 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Comment on mode of inheritance: For the phenotype pseudohypoparathyroidism, monoallelic and imprinted is the appropriate mode of inheritance as indicated. For the phenotype of McCune Albright syndrome, which includes polyostotic fibrous dysplasia, the mechanism is a post-zygotic variant leading to a somatic mosaic picture. The mode of inheritance is therefore still best matched to monoallelic, however depending on the level of mosaicism in the tissue tested, the proportion of alleles with the variant could vary considerably (from 0-50%) and therefore the ability to detect it.

Created: 11 Jul 2017, 4:16 p.m.

Green List (high evidence)

Disease causing variants in the GNAS locus have differing expression panels. Pseudohypothyroidism Ia, Ib & Ic are all caused by GNAS variants arising in the maternal alleles, therefore, the mode of inheritance (MOI) for GNAS in these conditions should be monoallelic maternally imprinted. Pseudopseudohypoparathyroidism, OMIM:612463 and Osseous heteroplasia, progressive, OMIM:166350 are associated with variants in the paternal alleles therefore, the mode of inheritance for GNAS in these conditions should be monoallelic paternally imprinted. Because the Skeletal dysplasia panel is representing various phenotypes, the MOI has been set to monoallelic, imprinted status unknown.

Created: 13 Oct 2022, 5:42 p.m. | Last Modified: 13 Oct 2022, 5:42 p.m.

Panel Version: 2.222

Listed as associated with Skeletal Dysplasia by Gene Advisor (June 2016), Steve Abbs

Created: 27 Jul 2016, 9:36 a.m.

Comment on mode of inheritance: All monogenic except for ACTH-independent macronodular adrenal hyperplasia 219080 (isolated cases) & McCune-Albright syndrome, 174800 (somatic mosaic)

Created: 7 Jul 2016, 11:13 a.m.

Comment on list classification: Used diagnostically by Ana Beleza (Guy's and St Thomas' NHS Foundation Trust)

Created: 21 Jun 2016, 12:49 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Green List (high evidence)

Tier 1

Created: 17 Jun 2016, 8:04 a.m.

Mode of inheritance
Other - please specify in evaluation comments

Phenotypes
ACTH-independent macronodular adrenal hyperplasia 219080 IC ; McCune-Albright syndrome, somatic, mosaic 174800 ; Osseous heteroplasia, progressive 166350; Pseudohypoparathyroidism Ia 103580; Pseudohypoparathyroidism Ib 603233; Pseudohypoparathyroidism Ic 612462; Pseudopseudohypoparathyroidism 612463

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