ESPE Abstracts

Objective: Inactivating mutations in the gene encoding the alpha-subunit of Gs (GNAS) gene, which consists of exons 1-13 and encodes the alpha-subunit of the stimulatory G protein (Gsa), are associated with several clinical syndromes, including pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH).

Method: We documented patient clinical characteristics and performed targeted next-generation sequencing and Sanger sequencing. The standards and guidelines of the American College of Medical Genetics and Genomics were used to classify and interpret the pathogenicity of each genetic mutation detected.

Results: The current study presents 5 patients with different mutations within exons 1-13 of the GNAS gene and distinct clinical phenotypes (3 PHP1a, 1 PPHP, and 1 POH). These 5 patients harbored pathogenic mutations, including an intronic mutation (c.212+3_212+6delAAGT), two missense mutations (c.314C>T and c.308T>C), and a deletion (c.565_568delGACT), which included one missense (c.314C>T) and one splicing (c.721+2 G>A) mutation which were never reported previously.

Conclusions: This study conducted a phenotypic and molecular assessment of patients, with diagnoses of PHP, PPHP, or POH. PHP can be difficult to diagnose because its clinical phenotype is highly variable and Gsα activity is not routinely assessed or available. Therefore, sequence of the GNAS gene serve as a method of confirming the diagnosis of PHP. In addition, it is necessary for clinicians to distinguish heterotopic ossification in POH from the AHO phenotype.