Renal tubulopathies

Gene: GNAS

I don't know

Comment on list classification: 2 cases reported in PMID: 30312418

Created: 5 Sep 2019, 2:10 p.m. | Last Modified: 5 Sep 2019, 2:10 p.m.

Panel Version: 1.120

Linked to several disease phenotypes in OMIM but they don't appear relevant to a renal disease.

PMID: 30312418 Biebermann et al 2018 - two unrelated boys presenting with a new combination of clinical findings that suggest both gain and loss of Gαs function. Both unrelated patients presented severe asymptomatic infantile hyponatremia, skeletal and growth plate abnormalities, early onset pubertal development, and apparent PTH resistance in the proximal but not in the distal renal tubules. An identical heterozygous de novo variant (c.1136T>G; p.F376V) was found on the maternal GNAS allele in both patients.

They authors say the clinical phenotype suggests a gain of function at the vasopressin 2 receptor (V2R) and lutropin/choriogonadotropin receptor (LHCGR), yet increased serum PTH concentrations indicative of impaired proximal tubular PTH1 receptor (PTH1R) function

Created: 30 Aug 2019, 4:19 p.m. | Last Modified: 5 Sep 2019, 2:15 p.m.

Panel Version: 1.121

This gene was part of an initial gene list collated by Emma Ashton (NE Thames Regional Genetics laboratory, GOSH NHS Foundation Trust) January 2019 on behalf of the GMS Renal Specialist Test Group; Gene Symbol submitted: GNAS; Suggested initial gene rating: amber; Evidence for inclusion: Biebermann et al 2018; PMID: 30312418. Two male patient reported, both with c.1136T>G p.(Phe376Val) on maternal GNAS allele. Evidence for exclusion: none provided; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none provided; Other Comments: We currently screen GNAS for PPHA/AHO but not this phenotype;

Created: 3 Feb 2019, 11:32 a.m.

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

Phenotypes
Unexplained hyponatremia in infancy, severe early-onset gonadotrophin-independent precocious puberty and skeletal abnormalities.

Publications

• Biebermann et al 2018 PMID: 30312418

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments

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