Identification and Characterization of Novel FSHR Copy Number Variations Causing Premature Ovarian Insufficiency

Area of Science:

• Reproductive Endocrinology
• Human Genetics
• Molecular Biology

Background:

• Follicle stimulating hormone (FSH) is vital for human fertility and ovarian function.
• Alterations in the FSH receptor (FSHR) gene are linked to reproductive disorders like premature ovarian insufficiency (POI).

Purpose of the Study:

• To report a novel case of FSHR-related ovarian insufficiency.
• To characterize the genetic basis of the condition in a patient with primary amenorrhea and delayed puberty.

Main Methods:

• Genetic analysis including chromosomal microarray analysis (CMA) and exome sequencing.
• Long-range PCR and Sanger sequencing to confirm intragenic deletions in the FSHR gene.

Main Results:

• Identification of two compound heterozygous intragenic deletions in the FSHR gene (maternal exons 5-10, paternal exons 3-6).
• Confirmation of complete loss of function in both FSHR alleles.
• Correlation of the genetic findings with the patient's POI phenotype.

Conclusions:

• This case demonstrates a novel mechanism of FSHR dysfunction due to compound heterozygous deletions.
• Highlights the role of copy number variations (CNVs) in the etiology of POI.
• Recommends including CNV detection in the diagnostic evaluation for POI for improved patient management.