Lan Yu1, Mingwei Li2,3, Huijuan Zhang1, Qiaohua He1, Feng Wan1, Cuilian Zhang1, Fei Wang4. 1. Henan Joint International Research Laboratory of Reproductive Bioengineering, Henan Provincial People's Hospital, Henan Provincial Reproductive Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450003, Henan, China. 2. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui University of Science and Technology, Anhui, 232007, China. 3. Frontier Research Center, School of Medicine, Anhui University of Science and Technology, 168 Taifeng Road, Anhui, 232001, China. 4. Frontier Research Center, School of Medicine, Anhui University of Science and Technology, 168 Taifeng Road, Anhui, 232001, China. fwangbio@mail.ustc.edu.cn.
Abstract
PURPOSE: Diminished ovarian reserve (DOR) is associated with compromised fertility that affects approximately 10% of couples. Gene mutations are implicated in the pathogenesis of DOR. Here, we aimed to assess the clinical and genetic characteristics of two sisters with impaired fertility history. The two sisters showed DOR and suffered from recurrent pregnancy loss (RPL) in natural pregnancy and in vitro fertilization-embryo transfer (IVF-ET). METHODS: Whole exome sequencing (WES) was performed for the proband and pathogenic variants detected were validated by Sanger sequencing in all available family members. Minigene assay was performed to evaluate the impact of sequence variants on splicing effect. RESULTS: Two novel heterozygous variants on the HFM1 gene, c.1978-2A > C and c.2680 + 3_2680 + 4delAT, were observed in the two patients. The genotype of their parents was all heterozygous, while the unaffected sister and brother did not carry the variants. Both variants could produce alternative transcripts compared to wild-type counterparts, which might result in protein dysfunction. CONCLUSION: Our results demonstrated that the pathogenic splicing variants in HFM1 are associated with DOR in these two sisters. Mutations in HFM1 may contribute to RPL and poor IVF-ET outcomes because of descending quality and quantity of oocytes. The study enriched the genetic defect spectrum of DOR and understanding of the roles of HFM1 in female reproduction.
PURPOSE: Diminished ovarian reserve (DOR) is associated with compromised fertility that affects approximately 10% of couples. Gene mutations are implicated in the pathogenesis of DOR. Here, we aimed to assess the clinical and genetic characteristics of two sisters with impaired fertility history. The two sisters showed DOR and suffered from recurrent pregnancy loss (RPL) in natural pregnancy and in vitro fertilization-embryo transfer (IVF-ET). METHODS: Whole exome sequencing (WES) was performed for the proband and pathogenic variants detected were validated by Sanger sequencing in all available family members. Minigene assay was performed to evaluate the impact of sequence variants on splicing effect. RESULTS: Two novel heterozygous variants on the HFM1 gene, c.1978-2A > C and c.2680 + 3_2680 + 4delAT, were observed in the two patients. The genotype of their parents was all heterozygous, while the unaffected sister and brother did not carry the variants. Both variants could produce alternative transcripts compared to wild-type counterparts, which might result in protein dysfunction. CONCLUSION: Our results demonstrated that the pathogenic splicing variants in HFM1 are associated with DOR in these two sisters. Mutations in HFM1 may contribute to RPL and poor IVF-ET outcomes because of descending quality and quantity of oocytes. The study enriched the genetic defect spectrum of DOR and understanding of the roles of HFM1 in female reproduction.