A novel synonymous variant in exon 1 of GNAS gene results in a cryptic splice site and causes pseudohypoparathyroidism type 1A and pseudo-pseudohypoparathyroidism in a French family.

Abstract

INTRODUCTION:

Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) (Inactivating PTH/PTHrP Signaling Disorders type 2, IPPSD2) are two rare autosomal disorders caused by loss-of-function mutations on either maternal or paternal allele, respectively, in the imprinted GNAS gene, which encodes the α subunit of the ubiquitously-expressed stimulatory G protein (Gαs).

CASE PRESENTATION:

We investigated a synonymous GNAS variant NM_001077488.2: c.108C>A / p.(Val36=) identified in a family presenting with IPPSD2 phenotype. In silico splicing prediction algorithms were in favor of a deleterious effect of this variant, by creating a new donor splicing site. The GNAS expression studies in blood suggested haploinsufficiency and showed an alternate splice product demonstrating the unmasking of a cryptic site, leading to a 34 base pairs deletion and the creation of a probable unstable RNA.We present the first familial case of IPPSD2 caused by a pathogenic synonymous variant in GNAS gene.

• Authors: Andreea Apetrei, Arnaud Molin, Nicolas Gruchy, Manon Godin, Claire Bracquemart, Antoine Resbeut, Gaëlle Rey, Gwenaël Nadeau, Nicolas Richard
• Journal: Bone reports (Bone Rep) Vol. 14 Pg. 101073 (Jun 2021) ISSN: 2352-1872 [Print] United States
• PMID: 33997150 (Publication Type: Case Reports)
• Copyright: © 2021 Centre Hospitalier Universitaire de Caen. Published by Elsevier Inc.