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


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


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


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


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.


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


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


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

From: Disorders of GNAS Inactivation

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