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

• Published in: Bone reports Vol. 14; p. 101073
• Main Authors: Apetrei, Andreea, Molin, Arnaud, Gruchy, Nicolas, Godin, Manon, Bracquemart, Claire, Resbeut, Antoine, Rey, Gaëlle, Nadeau, Gwenaël, Richard, Nicolas
• Format: Report
• Language: English
• Published: 01.06.2021
• ISSN: 2352-1872; 2352-1872
• DOI: 10.1016/j.bonr.2021.101073

INTRODUCTIONPseudohypoparathyroidism 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 PRESENTATIONWe 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.