Abstract: Objective To investigate whether multiple gene mutations were existed to cause congenital hypogonadotropic hypogonadism(CHH), by screening genes in CHH patients with FGFR1 mutations. Methods FGFR1 mutations were identified in 15 CHH patients. Other CHH-related genes were screened in these patients. Bioinformatics software was used to analyze the pathogenicity of gene variant. Results 1)Mutations in FGFR1 were inherited from parents in 9 patients (inherited mutation group)in spite of the fact, their parents showed normal reproductive axis function. 2)In the inherited mutation group, 6 patients harbored another mutation including PROKR2(W178S), FGF8(T121N), HS6ST1(P242L), SEMA3A(R734W), LZTR1(Q10Rfs*15) and FGFR1 compound heterozygous mutation. Multiple gene mutations may lead to CHH. 3)Six patients were found to have de novo mutations in FGFR1(de novo mutation group) but not no other pathogenic CHH related gene mutations. Conclusions FGFR1 mutations inherited from parents may require another blow from CHH-related genes to cause CHH. This study expands our understanding of the pathogenesis of CHH caused by digenic mutation.

Key words: congenital hypogonadotropic hypogonadism(CHH), fibroblast growth factor receptor 1(FGFR1), digenic mutation