Genotype-phenotype correlation in fibrous dysplasia/McCune-Albright syndrome.

CONTEXT Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone and endocrine disorder resulting in fractures, pain, and disability. There are no targeted or effective therapies to alter the disease course. Disease arises from somatic gain-of-function variants at the R201 codon in GNAS, replacing arginine by either cysteine or histidine. The relative pathogenicity of these variants is not fully understood. OBJECTIVE 1) To determine whether the most common GNAS variants (R201C and R201H) are associated with a specific clinical phenotype, and 2) to determine the prevalence of the most common GNAS variants in a large patient cohort. DESIGN Retrospective cross-sectional analysis. MAIN OUTCOME MEASURES Correlation between genotype and phenotype characterized by clinical, biochemical, and radiographic data. RESULTS Sixty-one subjects were genotyped using DNA extracted from tissue or circulating cell-free DNA. Twenty-two subjects (36.1%) had the R201C variant, and 39 (63.9%) had the R201H variant. FD skeletal disease burden, hypophosphatemia prevalence, fracture incidence, and ambulation status were similar between the two groups. There was no difference in the prevalence of endocrinopathies, ultrasonographic gonadal or thyroid abnormalities, or pancreatic involvement. There was a non-significant association of cancer with the R201H variant. CONCLUSION There is no clear genotype-phenotype correlation in patients with the most common FD/MAS pathogenic variants. The predominance of the R201H variant observed in our cohort and reported in the literature indicates it is likely responsible for a larger burden of disease in the overall population of patients with FD/MAS, which may have important implications for future development of targeted therapies.