Identification of Novel and Rare GNAS Mutations in Craniofacial Fibrous Dysplasia

ABSTRACT Background Fibrous dysplasia (FD), caused by activating mutations of GNAS , is a skeletal disorder with considerable clinicopathological heterogeneity. Although prevalent mutations such as R201C and R201H dominate in FD, a limited number of rare mutations, including R201S, R201G, and Q227L, have been documented. The scarcity of information concerning these uncommon mutations motivates our investigation, seeking to enhance comprehension of this less‐explored subgroup within FD. Methods This study introduces three cases of craniofacial FD exhibiting rare GNAS mutations. Employing DNA sequencing on fresh frozen lesion tissues, we conducted a thorough analysis of clinical, radiological, and pathological features, delving into genotypic and phenotypic correlations. A comparative assessment with our previous series was also conducted. Results In the subset of patients subjected to DNA sequencing, a novel GNAS missense mutation (Q227E) was identified in one case, while a rare GNAS mutation (R201S) in exon 8 was found in the other two patients. Although no apparent phenotypic distinctions were observed among those with GNAS hotspot mutations (R201C, R201H), a more severe phenotype was discerned in the case featuring the novel GNAS mutation Q227E. Conclusions This study marks the first report of the Q227E mutation in the GNAS gene associated with bone disease, enriching our understanding of FD's genetic basis and shedding light on the clinicopathological heterogeneity of craniofacial FD.