Table 2.

Phenotypes and Genetic Mechanisms of Disorders of GNAS Inactivation

PhenotypeEndocrine DefectsClinical FeaturesOther FeaturesParental Origin of the Inactivated GNAS AlleleMolecular Defect 1
PHP-IaMultihormone resistance 2AHO 3; early-onset obesityCognitive disabilityMaternalHeterozygous GNAS pathogenic variant in exons 1-12 4, 5
PHP-IcMultihormone resistance 2AHOCognitive disabilityMaternalHeterozygous GNAS pathogenic variant in exon 13 6
PHP-IbPTH resistance; partial TSH resistance in someEnhanced intrauterine growth 7; mild brachydactyly in someLoss of methylation in exon A/B 1, 7 (familial)MaternalImprinting defect: heterozygous deletion of STX16 or regulatory elements in GNAS complex locus 1, 8 (familial)
Variable degrees of a more global defect in methylation at multiple DMRs 3, 4 (sporadic)Paternal 20q disomy or unknown epigenetic defect (sporadic4
PPHPNoneAHO; IUGR 9PaternalHeterozygous GNAS pathogenic variant 4, 5
Progressive osseous heteroplasiaNoneProgressive heterotopic ossification extending to deep connective tissuesPaternalHeterozygous GNAS pathogenic variant 4
Osteoma cutisNoneHeterotopic ossification limited to dermis & subcutaneous tissuesPaternalHeterozygous GNAS pathogenic variant 4

AHO = Albright hereditary osteodystrophy; DMR = differentially methylated region; IUGR = intrauterine growth restriction; PHP = pseudohypoparathyroidism; PTH = parathyroid hormone; TSH = thyroid-stimulating hormone

1.

See Molecular Genetics and Figure 1 for details of the structure and expression of the GNAS complex locus.

2.

Multiple hormone resistance, resistance to PTH, TSH, and GHRH; often gonadotropins (LH and FSH) as well

3.

AHO comprising round face, short stature, brachydactyly/brachymetacarpia, and heterotopic ossification

4.
5.

Chromosome abnormalities of GNAS-related disorders are uncommon; however, Aldred et al [2002] described two individuals with full deletions of GNAS due to interstitial chromosome deletions: one with a maternally derived deletion of chromosome 20q13.31-q13.33 and a diagnosis of PHP-Ia and the other with a paternally inherited deletion of chromosome 20q13.13-q13.32 and a diagnosis of PPHP.

6.

Impairs coupling of Gsα to heptahelical receptors. See Molecular Genetics.

7.
8.

STX16 and DMRs associated with GNAS exons designated NESP and GNAS-AS1. See Figure 1; Elli et al [2013a] and references therein.

9.

Associated mainly with pathogenic variants in GNAS exons 2-13 [Richard et al 2013]

From: Disorders of GNAS Inactivation

Cover of GeneReviews®
GeneReviews® [Internet].
Adam MP, Feldman J, Mirzaa GM, et al., editors.
Seattle (WA): University of Washington, Seattle; 1993-2024.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.