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

Abstract

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 <i>GNAS</i> gene, which encodes the α subunit of the ubiquitously-expressed stimulatory G protein (Gαs). We investigated a synonymous <i>GNAS</i> variant NM_001077488.2: c.108C>A / p.(Val36=) identified in a family presenting with IPPSD2 phenotype. <i>In silico</i> splicing prediction algorithms were in favor of a deleterious effect of this variant, by creating a new donor splicing site. The <i>GNAS</i> 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 <i>GNAS</i> gene.