Mutations paternelles de GNAS : quels phénotypes ? Quel conseil génétique ?

Abstract

Parental imprinting and the type of the genetic alteration play a determinant role in the phenotype expression of GNAS locus associated to pseudohypoparathyroidism (PHP). GNAS locus gives rise to several different messenger RNA transcripts that are derived from the paternal allele, the maternal allele, or both and can be either coding or non-coding. As a consequence, GNAS mutations lead to a wide spectrum of phenotypes. An alteration in the coding sequence of the gene leads to a haplo-insufficiency and a dysmorphic phenotype (Albright's syndrome or AHO). AHO is a clinical syndrome defined by specific physical features including short stature, obesity, round-shaped face, subcutaneous ossifications, brachymetarcapy (mainly of the 4th and 5th ray). If the alteration is on the maternal allele, there is a hormonal resistance to the PTH at the kidney level and to the TSH at the thyroid level. The phenotype is known as pseudohypoparathyroidism type 1a (PHP1a). If the alteration is on the paternal allele, there are few clinical signs with no hormonal resistance and the phenotype is known as pseudopseudo hypoparathyroidism (pseudo-PPHP). Heterozygous GNAS mutations on the paternal GNAS allele were associated with intra uterin growth retardation (IUGR). Moreover, birth weights were lower with paternal GNAS mutations affecting exon 2-13 than with exon 1/intron 1 mutations suggesting a role for loss of function XLαs. Progressive osseous heteroplasia (POH) is a rare disease of ectopic bone formation, characterized by cutaneous and subcutaneous ossifications progressing towards deep connective and muscular tissues. POH is caused by a heterozygous GNAS inactivating mutation and has been associated with paternal inheritance. However, genotype/phenotype correlations suggest that there is no direct correlation between the ossifying process and parental origin, as there is high variability in heterotopic ossification. Clinical heterogeneity makes genetic counseling a very delicate matter, specifically where paternal inheritance is concerned as it can lead either to a mild expression of pseudo-PHP or to a severe one of POH.