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
Andreea Apetrei,
Arnaud Molin,
Nicolas Gruchy,
Manon Godin,
Claire Bracquemart,
Antoine Resbeut,
Gaëlle Rey,
Gwenaël Nadeau,
Nicolas Richard
Affiliations
Andreea Apetrei
Normandy University, UNICAEN, Caen University Hospital, Department of Genetics, Reference Center of Rare Diseases of Calcium and Phosphorus Metabolism, EA 7450 BioTARGen, Caen, France
Arnaud Molin
Normandy University, UNICAEN, Caen University Hospital, Department of Genetics, Reference Center of Rare Diseases of Calcium and Phosphorus Metabolism, EA 7450 BioTARGen, Caen, France
Nicolas Gruchy
Normandy University, UNICAEN, Caen University Hospital, Department of Genetics, Reference Center of Rare Diseases of Calcium and Phosphorus Metabolism, EA 7450 BioTARGen, Caen, France
Manon Godin
Normandy University, UNICAEN, Caen University Hospital, Department of Genetics, Reference Center of Rare Diseases of Calcium and Phosphorus Metabolism, EA 7450 BioTARGen, Caen, France
Claire Bracquemart
Normandy University, UNICAEN, Caen University Hospital, Department of Genetics, Reference Center of Rare Diseases of Calcium and Phosphorus Metabolism, EA 7450 BioTARGen, Caen, France
Antoine Resbeut
Normandy University, UNICAEN, Caen University Hospital, Department of Genetics, Reference Center of Rare Diseases of Calcium and Phosphorus Metabolism, EA 7450 BioTARGen, Caen, France
Gaëlle Rey
Metropole Savoie Hospital Center, Genetics Department, Chambéry, France
Gwenaël Nadeau
Metropole Savoie Hospital Center, Genetics Department, Chambéry, France
Nicolas Richard
Normandy University, UNICAEN, Caen University Hospital, Department of Genetics, Reference Center of Rare Diseases of Calcium and Phosphorus Metabolism, EA 7450 BioTARGen, Caen, France; Corresponding author.
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.
