Identification of compound heterozygous variants in MSH4 as a novel genetic cause of diminished ovarian reserve

BACKGROUND: Diminished ovarian reserve (DOR) is a common cause of female infertility, with genetic factors being a significant contributor. However, due to high genetic heterogeneity, the etiology of DOR in many cases remains unknown. In this study, we analyzed the phenotype of a young woman with primary infertility and performed molecular genetic analysis to identify the genetic cause of her condition, thus providing important insights for genetic counseling and reproductive guidance. METHODS: We collected the patient’s basic information, clinical data, as well as diagnostic and therapeutic history and performed whole-exome sequencing on her peripheral blood. Candidate pathogenic variants were validated by Sanger sequencing in family members, and the pathogenicity of variants was analyzed using ACMG guidelines. We used bioinformatics tools to predict variant effects on splicing and protein function, and performed in vitro experiments including minigene assay and expression analysis to evaluate their functional effects on HEK293T. RESULTS: We identified biallelic MSH4 variants, c.2374 A > G (p.Thr792Ala) and c.2222_2225delAAGA (p.Lys741Argfs*2) in the DOR patient. According to ACMG guidelines, the former was classified as likely pathogenic, while the latter was classified as pathogenic. The patient presented with poor oocyte quantity and quality, resulting in unsuccessful in vitro fertilization cycles. Bioinformatics and in vitro functional analysis showed that the c.2374 A > G variant altered the local conformation of the MutS_V domain without decreasing MSH4 protein expression, while the c.2222_2225delAAGA variant led to a reduction in MSH4 protein expression without impacting splicing. CONCLUSIONS: In this study, we present evidence of biallelic variants in MSH4 as a potential cause of DOR. Our findings indicate a correlation between MSH4 variants and reduced oocyte quality, as well as abnormal morphology of the first polar body, thereby expanding the phenotypic spectrum associated with MSH4 variants. Furthermore, Our study emphasizes the importance of utilizing whole-exome sequencing and functional analysis in diagnosing genetic causes, as well as providing effective genetic counseling and reproductive guidance for DOR patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12958-023-01127-0.