Pathogenic Variants in ZSWIM7 Cause Primary Ovarian Insufficiency

Context Primary ovarian insufficiency (POI) is a genetically heterogeneous condition associated with infertility and an increased risk of comorbidities. An increased number of genes implicated in DNA damage response pathways has been associated with POI as well as predisposition to cancers. Objective We sought to identify and characterize patients affected by POI caused by pathogenic variants in genes involved in DNA damage response during meiosis. Setting Study subjects were recruited at academic centers. Patients or Other Participants Individuals with a diagnosis of POI and their family members were enrolled for genetic analysis. Clinical findings, family history, and peripheral blood samples were collected. Research design Exome sequencing was performed on the study participants and their family members (when available). Protein conservation analysis and in silico modeling were used to obtain the structural model of the detected variants in the ZSWIM7 gene. Main Outcome Measure(s) Rare deleterious variants in known and candidate genes associated with POI. Results Homozygous deleterious variants in the ZSWIM7 gene were identified in 2 unrelated patients with amenorrhea, an absence of puberty, and prepubertal ovaries and uterus. Observed variants were shown to alter the ZSWIM7 DNA-binding region, possibly affecting its function. Conclusions Our study highlights the pivotal role of the ZSWIM7 gene involved in DNA damage response during meiosis on ovarian development and function. Characterization of patients with defects in DNA repair genes has important diagnostic and prognostic consequences for clinical management and reproductive decisions.

Automated summary

This study identified pathogenic variants in the ZSWIM7 gene associated with primary ovarian insufficiency (POI), highlighting the importance of this gene in DNA damage response during meiosis and its role in ovarian development and function. Characterization of patients with defects in DNA repair genes has important diagnostic and prognostic consequences for clinical management and reproductive decisions.