Next-generation sequencing of 500 POI patients identified novel responsible monogenic and oligogenic variants

Abstract Background Premature ovarian insufficiency refers to the loss of ovarian function before 40 years of age. The etiology is heterogeneous, and genetic factors account for 20–25% of cases. However, how to transform genetic findings to clinical molecular diagnose remains a challenge. To identify potential causative variations for POI, a next generation sequencing panel with 28 known causative genes of POI was designed, and a large cohort of 500 Chinese Han patients was screened directly. Pathogenic evaluation of the identified variants and the phenotype analysis were performed according to monogenic or oligogenic variants. Results A total of 14.4% (72/500) of the patients carried 61 pathogenic or likely pathogenic variants in 19 of the genes in the panel. Interestingly, 58 variants (95.1%, 58/61) were firstly identified in patients with POI. FOXL2 harbored the highest occurrence frequency (3.2%, 16/500), among whom presented with isolated ovarian insufficiency instead of blepharophimosis-ptosis-epicanthus inversus syndrome. Moreover, luciferase reporter assay confirmed variant p.R349G, which account for 2.6% of POI cases, impaired the transcriptional repressive effect of FOXL2 on CYP17A1 . The novel compound heterozygous variants in NOBOX and MSH4 were confirmed by pedigree haplotype analysis, and digenic heterozygous variants in MSH4 and MSH5 were firstly identified. Furthermore, nine patients (1.8%, 9/500) with digenic or multigenic pathogenic variants presented with delayed menarche, early onset of POI and high prevalence of primary amenorrhea compared with those with monogenic variation(s). Conclusions The genetic architecture of POI has been enriched through the targeted gene panel in a large cohort of patients with POI. Specific variants in pleiotropic genes may result in isolated POI rather than syndromic POI, whereas oligogenic defects might have cumulative deleterious effects on the severity of POI phenotype.