Congenital hypothyroidism

Gene: GNAS

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: 6 Dec 2024, 11:30 a.m. | Last Modified: 6 Dec 2024, 11:30 a.m.

Panel Version: 2.20

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

Pseudohypothyroidism Ia & Ic are caused by GNAS variants arising in the maternal alleles, therefore the paternal alleles are imprinted. In Pseudohypothyroidism Ib the imprinting of the maternal allele is disrupted by deletions in STX16. Therefore, the mode of inheritance for GNAS in this panel should be monoallelic, imprinted status unknown as either allele could be imprinted.

Created: 13 Oct 2022, 12:23 p.m. | Last Modified: 13 Oct 2022, 5:26 p.m.

Panel Version: 2.13

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

PMID: 23412865 (Alvest et al., 2013) identify a GNAS mutation in Brazilian boy presenting with primary hypothyroidism and a diagnosis of pseudohypoparathyroidism-Ia. Molecular analysis revealed a novel missense mutation in GNAS exon 1 (TCG→CGC, C3R) in both the child and his (affected?) mother.

Created: 14 Feb 2017, 5:39 p.m.

Comment on list classification: Updated rating from Red to Green: Recommended for prior genetic testing plus >3 cases linked to MIM:103580, which presents with hypothyroidism.

Created: 14 Feb 2017, 5:38 p.m.

Romanet et al., 2015 (PMID:25802348) report a case of Pseudohypoparathyroidism (PHP) caused by epigenetic (methylation) changes in GNAS in a patient with congenital hypothyroidism.

Created: 14 Feb 2017, 3:23 p.m.

Comment on mode of inheritance: On GeCIP imprinting list.

Created: 13 Feb 2017, 3:21 p.m.

PMID:27922245 (Kirel et al., 2016) report a heterozygous mutation in the GNAS gene (IVS4+5G>C) in two related patients: a boy wtih PHP type Ia and his mother with pseudoPHP. The boy was first diagnosed as having primary hypothyroidism at 2.5 months.

Created: 13 Feb 2017, 3:18 p.m.

PMC:3961212 (Wu et al. 2014) studied 7 patients from 5 families including 6 patients with PHP1A. 5 of the PHP1A patients had primary hypothyroidism with elevated TSH levels. They report 5 new GNAS mutations across 5 families: c.85C>T (p.Q29*), c.103C>T (p.Q35*), c.840-2A>G (p.R280Sfs*21), c.1027_1028delGA (p.D343*), and c.1174G>A (p.E392K).

Created: 13 Feb 2017, 3:13 p.m.

In a 10-year-old Caucasian girl with brachymetacarpia, mental retardation, normocalcemic pseudohypoparathyroidism, and hypothyroidism (MIM:103580), Thiele et al.2007 (PMID:17299070) identified a heterozygous insertion of an adenosine in exon 3 of the GNAS gene.

Created: 13 Feb 2017, 3:02 p.m.

Comment on phenotypes: Hypothyroidism is a particular condition observed in pseudohypoparathyroidism (PHP), and congenital hypothryoidism can provide an early diagnostic clue for PHP1A (Source: PMID:25591844).

Created: 13 Feb 2017, 2:49 p.m.