Genetic And Clinical Analysis Of 76 Patients With Birt-Hogg-Dubé Syndrome

Objective: To summarize the epidemiological characteristics,genetic and clinical characteristics of an autosomal dominant inherited disorder,Birt-Hogg-Dubésyndrome(BHDS);and to investigate the relationship between genotypes and phenotypes in BHDS in order to improve the understanding and management of this disease.Methods: We collected the clinical data of BHDS patients diagnosed in our hospital from January 1,2017 to December 31,2022 and analyzed the phenotypic features of patients with exons 1-3 deletion to compare with those of point mutations carriers.Results: There were 76 patients from 50 unrelated families enrolled in this study.The prevalence of BHDS patients diagnosed in Anhui Province was 1.24 cases per million,much higher than that of 0.20 cases per million in China,which in Feidong County was 50.5 times more than those in China.Twenty unique point mutations(including 5 novel mutations)were detected in 65 patients from 45 families(90%).Exons 1-3 deletion were identified in 11 patients from 5 families(10%)that resided in the same region,Feidong County of Anhui Province,China.Bidirectional sequencing of the junction showed a 7,543 bp deletion encompassing exons 1-3.Breakpoint analysis indicated that two Alu repeats(Alu-Sz,Alu-Sc)and a 23 bp stretch of microhomology were involved in the deletion boundaries.The prevalence of exons 1-3 deletion carriers in Feidong County was 8.1-times higher than that for BHDS in Anhui Province,suggesting a clustered phenomenon of exons 1-3 deletion.The average age of patients with exons 1-3 deletion and those with point mutations were 47±12 years and 44±14 years,respectively.No significant difference was found between two groups in age,gender and smoking history(P > 0.05).Exons 1-3deletion was associated with a 91% risk for pneumothorax(10/11),significantly higher than point mutations(91% vs.58%,P < 0.05).The risk of renal cancer may be higher in those with exons 1-3 deletion than for those with point mutations(18% vs.4%,P > 0.05),while the prevalence of skin lesions in two groups were similar(89%vs.78%,P > 0.05).Conclusion: The prevalence of BHDS patients in Anhui Province and Feidong County is 6 and 50-fold higher than those reported in other places of China,respectively.Large intragenic deletion of exons 1-3 in FLCN was identified as a local aggregation phenomenon in Feidong County,China,which might result from founder effect.Exons 1-3 deletion was associated with a significantly higher risk of pneumothorax compared to those with point mutations.Further studies were warranted to explore the relationship between renal cancer and genotype.