Identification of the first homozygous POLG mutation causing non-syndromic ovarian dysfunction

To investigate the genetic cause of non-syndromic ovarian dysfunction in a patient from a consanguineous family.

This study examined a patient with irregular menstrual cycles and abnormal oocytes. The patient had undergone irregular hormone replacement therapy over 3 years to adjust the menstrual cycle and improve ovarian function. Prior to ovarian stimulation in our hospital, 3 months of androgen and regular hormone therapy were used as an intervention method. No follicular development was detected in the subsequent three cycles using letrozole treatment. The patient then received a constantly adjusted dose of menotropins, but produced only one oocyte.

Whole-exome sequencing analysis identified the first homozygous POLG mutation (c.2890C > T; p.R964C) associated with ovarian dysfunction. Sanger sequencing was used to validate. In silico analysis suggested that the p.R964C mutation was pathogenic. Conservation analysis demonstrated that R964 was an important site for the DNA polymerase function of POLG.

Biallelic mutations in POLG may be associated with ovarian dysfunction. This study has improved our understanding of POLG-related genetic mutations in ovarian dysfunction, and the mode of inheritance of certain sequence variants. This information will assist genetic counseling and precision medicine in the future.