Genetic Variants in Idiopathic Premature Ovarian Insufficiency

Investigation of Pathogenic Variants in DNA Repair and Meiotic Genes Associated With Ovarian Reserve and Folliculogenesis in Idiopathic Premature Ovarian Insufficiency Using Whole Exome Sequencing: A Case-Control Study

Premature ovarian insufficiency is a condition in which ovarian function decreases or is lost before the age of 40 years. In many patients, the underlying cause remains unexplained. This prospective observational case-control study aims to investigate pathogenic and likely pathogenic genetic variants in DNA repair and meiotic genes related to ovarian reserve and folliculogenesis in women with idiopathic premature ovarian insufficiency.

The study will include women younger than 40 years with idiopathic premature ovarian insufficiency and age- and ethnicity-matched control participants with normal ovarian function. Clinical and reproductive data will be collected, and a peripheral blood sample will be obtained from each participant for whole exome sequencing. The frequency of pathogenic or likely pathogenic variants will be compared between the case and control groups. No investigational drug, device, or treatment intervention will be administered.

Inclusion Criteria:

For the idiopathic premature ovarian insufficiency group:

• Women aged 18 to 39 years.
• Spontaneous amenorrhea or marked menstrual irregularity lasting at least 4 months.
• Serum FSH level greater than 25 IU/L. In cases of diagnostic uncertainty, FSH measurement may be repeated after 4 to 6 weeks.
• Diagnosis of idiopathic premature ovarian insufficiency, with no known chromosomal abnormality, FMR1 premutation, defined syndromic genetic diagnosis, or iatrogenic cause.
• Willingness to participate in the study and ability to provide written informed consent.

For the control group:

• Women aged 18 to 39 years.
• Regular menstrual cycles.
• Age-appropriate normal ovarian reserve findings, including FSH and AMH values within age-appropriate reference ranges and, when available, appropriate antral follicle count.
• No known history of infertility, premature ovarian insufficiency, or early menopause.
• No history of gonadotoxic treatment or ovarian surgery.
• Willingness to participate in the study and ability to provide written informed consent.

Exclusion Criteria:

For both groups:

• Known chromosomal abnormality, such as Turner syndrome or structural X chromosome abnormality.
• FMR1 premutation carrier status.
• Previously defined syndromic genetic diagnosis.
• Active malignancy.
• History of gonadotoxic chemotherapy or pelvic radiotherapy.
• Iatrogenic ovarian damage or iatrogenic premature ovarian insufficiency after ovarian surgery.
• Clear autoimmune, endocrine, or other clinical condition that may explain secondary amenorrhea.
• Refusal to provide informed consent or request to withdraw study data.
• Insufficient DNA sample quality or inability to complete genetic analysis for technical reasons.

Additional exclusion criteria for the control group:

• Known history of infertility, premature ovarian insufficiency, or early menopause.
• Ovarian reserve findings below the expected range for age.
• Previous gonadotoxic treatment or ovarian surgery.