Abstract

Background Premature ovarian insufficiency (POI) leads to early loss of ovarian function in women aged < 40 years and is highly heterogeneous in etiology. The genetic etiology of this disorder remains unknown in most women with POI. Methods Whole-exome sequencing (WES) was used to analyze genetic factors within a Chinese POI pedigree. Bioinformatic analysis was applied to identify the potential genetic cause, and Sanger sequencing confirmed the existence of a mutation within the pedigree. A minigene assay was performed to validate the effect of the mutation on pre-mRNA splicing. Results A novel heterozygous missense mutation in HFM1 (c.3470G > A) associated with POI was identified by whole-exome sequencing. This mutation was heterozygous in the affected family members and was absent in the unaffected family members. In silico analysis predicted that the mutation was potentially pathogenic. Bioinformatic splice prediction tools revealed that the mutation was very likely to have a strong impact on splice site function. Results of the minigene assay revealed that the mutation changed the mRNA splicing repertory. Conclusions The missense mutation of the HFM1 gene (c.3470G > A) may be a cause of POI. The mutation altered mRNA splicing in cells. This study can provide geneticists with deeper insight into the pathogenesis of POI and aid clinicians in making early diagnoses in affected women.