Landscape of pathogenic mutations in premature ovarian insufficiency

Area of Science:

• Genetics
• Reproductive Biology
• Endocrinology

Background:

• Premature ovarian insufficiency (POI) is a significant cause of female infertility, characterized by the early loss of ovarian function.
• The molecular basis of POI is complex and not fully understood, necessitating further genetic investigation.

Purpose of the Study:

• To identify genetic variants associated with premature ovarian insufficiency (POI).
• To expand the understanding of the genetic landscape underlying POI and its contribution to female infertility.

Main Methods:

• Whole-exome sequencing was performed on a cohort of 1,030 patients diagnosed with POI.
• Association analyses were conducted comparing the POI cohort with a control group of 5,000 individuals without POI.

Main Results:

• 195 pathogenic/likely pathogenic variants were found in 59 known POI-causative genes, explaining 18.7% of cases.
• Association analyses identified 20 novel POI-associated genes, with significant burden of loss-of-function variants.
• Pathogenic variants in known and novel genes collectively accounted for 23.5% of POI cases.
• Genetic contribution to POI was higher in patients with primary amenorrhea than secondary amenorrhea.

Conclusions:

• This study significantly expands the catalog of genes associated with premature ovarian insufficiency (POI).
• The identified genes are involved in critical ovarian functions, including development, meiosis, and folliculogenesis.
• These findings offer potential for improved genetic screening and diagnosis of POI, aiding in understanding female infertility.